Imipritone for glioma
阅读说明：本技术 用于胶质瘤的依米立酮 (Imipritone for glioma ) 是由 J·E·艾伦 M·斯托尼 V·V·普拉布 于 2018-11-05 设计创作，主要内容包括：依米立酮(imipridone)选择性地调节A类G蛋白偶联受体(GPCR),如多巴胺受体的D2样亚家族,并且可用于治疗需要这种调节的病状和病症,如癌症。具体地,所述癌症涉及大脑的中线结构、具有组蛋白H3突变的癌症或两者。另外,提供了鉴别患有这些病状的受试者是否可能对如依米立酮施用等治疗方案作出应答的方法。此外,还提供了评估如依米立酮施用等治疗方案的有效性、监测患有这些病状的受试者或为患有这些病状的受试者提供预后的方法。(Imiperidone (imipridone) selectively modulates class a G protein-coupled receptors (GPCRs), such as the D2-like subfamily of dopamine receptors, and is useful for treating conditions and disorders requiring such modulation, such as cancer. In particular, the cancer involves the midline structure of the brain, a cancer with a histone H3 mutation, or both. In addition, methods of identifying whether a subject having these conditions is likely to respond to a treatment regimen such as administration of isomiridone are provided. In addition, methods of assessing the effectiveness of a treatment regimen, such as administration of emiperidone, monitoring subjects having these conditions, or providing a prognosis for subjects having these conditions are also provided.)
1. A method of treating or preventing cancer in a subject in need thereof, the method comprising: administering to said subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of compound (1)
Or a pharmaceutically acceptable salt thereof, wherein the cancer involves the midline structure of the brain and has a histone H3K 27M mutation.
2. The method of claim 1, wherein the cancer involves the thalamus, medulla, hypothalamus, basal ganglia, pineal gland, midbrain, cerebellum, pons or spinal cord.
3. The method of claim 1, wherein the histone H3K 27M mutation is H3.3K 27M or H3.1K27M.
4. The method of claim 1, wherein the histone H3K 27M mutation is in one or more histone genes selected from: H3F3A, H3F3B, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, or HIST1H 3J.
5. The method of claim 1, wherein DRD2 is overexpressed, DRD5 is underexpressed, or both, in cancer tissue.
6. The method of claim 1, wherein the subject is a human.
7. The method of claim 1, wherein the subject is a domestic pet.
8. The method of claim 1, wherein the subject is a pediatric subject.
9. A method of treating or preventing cancer in a subject in need thereof, the method comprising: administering to the subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (10) or an analog or pharmaceutically acceptable salt thereof, wherein the cancer has a histone H3 mutation.
10. The method of claim 9, wherein the cancer is selected from the group consisting of: central nervous system tumors, brain tumors, peripheral nervous system tumors, pheochromocytoma, paraganglioma, adrenocortical carcinoma, adrenal tumors, and neuroendocrine tumors.
11. The method of claim 9, wherein the cancer is from a glial cell and is selected from the group consisting of: meningioma, ependymoma, oligodendroglioma, astrocytoma, optic glioma, pinealoma, rhabdoid tumor, and diffuse endogenous pontine glioma; or wherein the cancer is from a neural cell and is selected from the group consisting of: medulloblastoma, neuroblastoma, ganglioneuroma, primitive neuroectodermal tumors, and schwannoma.
12. The method of claim 9, wherein the cancer involves the thalamus, medulla, hypothalamus, basal ganglia, pineal gland, midbrain, cerebellum, pons or spinal cord.
13. The method of claim 9, wherein the histone H3 mutation is H3.3K 27M or H3.1K 27M.
14. The method of claim 9, wherein the cancer has a K27M mutation in one or more histone genes selected from: H3F3A, H3F3B, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, or HIST1H 3J.
15. The method of claim 9, wherein DRD2 is overexpressed in cancer tissues, DRD5 is underexpressed, or both.
16. The method of claim 9, wherein the subject is a human.
17. The method of claim 9, wherein the subject is a domestic pet.
18. The method of claim 9, wherein the compound is ONC 201.
19. The method of claim 9, wherein the subject is a pediatric subject.
20. A method of treating or preventing cancer in a subject in need thereof, the method comprising: administering to the subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (10) or an analog or pharmaceutically acceptable salt thereof, wherein the cancer involves the midline structure of the brain.
21. The method of claim 20, wherein the cancer involves the thalamus, medulla, hypothalamus, basal ganglia, pineal gland, midbrain, cerebellum, pons or spinal cord.
22. The method of claim 20, wherein the cancer has a histone H3 mutation, wherein the histone H3 mutation is H3.3K 27M or H3.1K 27M.
23. The method of claim 20, wherein the cancer has a histone H3K 27M mutation in one or more histone genes selected from: H3F3A, H3F3B, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, or HIST1H 3J.
24. The method of claim 20, wherein DRD2 is overexpressed in cancer tissues, DRD5 is underexpressed, or both.
25. The method of claim 20, wherein the subject is a human.
26. The method of claim 20, wherein the subject is a domestic pet.
27. The method of claim 20, wherein the compound is ONC 201.
28. The method of claim 20, wherein the subject is a pediatric subject.
Background
ONC201 (7-benzyl-4- (2-methylbenzyl) -1,2,6,7,8, 9-hexahydroimidazo [1,2-a ] pyrido [3,4-e ] pyrimidin-5 (1H) -one) is a founder member of a class of anticancer compounds called imiripone (imiprodone) in phase II clinical trials of a variety of advanced cancers. Since the discovery that the compound is a p 53-independent inducer of TRAIL gene transcription, preclinical studies have shown that it has anti-proliferative and pro-apoptotic effects on a wide range of tumor cells, but not normal cells. Its mechanism of action involves PERK-independent activation involved in an integrated stress response, leading to DR5 tumor upregulation and dual Akt/ERK inactivation, and subsequent Foxo3a activation leading to death ligand TRAIL upregulation. ONC201 has oral activity in animal models with infrequent dosing, induces sustained pharmacodynamic effects, and is free of genotoxicity. The first clinical trial of ONC201 in humans in advanced invasive refractory solid tumors confirmed its well-tolerated nature.
H3K 27M (a specific mutation of the histone H3 protein) was found to occur as an oncogenic mutation in the context of cancers involving the midline structure of the brain, i.e., the thalamus, medulla, hypothalamus, basal ganglia, pineal, midbrain, cerebellum, pons or spinal cord. These tumors have not been surgically operable (particularly in the brainstem where the pons are located) because of their location (the brain regions involved in critical physiological functions). This means that until recently, midline gliomas such as diffuse endogenous brain bridge glioma (DIPG) were diagnosed only on the basis of radiographic images. Advances in neurosurgical technology and increased parental consent for post-mortem tumor tissue extraction have resulted in the availability of sufficient biological samples to allow systematic genomic assessment of DIPG and other midline gliomas. Gliomas in the midline of the brain belong to the most aggressive primary malignant brain cancer type. The disease is derived from glial cells that form tissues that surround and protect other nerve cells found in the brain and spinal cord.
Standard therapy for midline gliomas involves neurosurgery, where feasible, followed by fractionated external beam radiotherapy. Due to location, invasiveness and low survival time in the brain, gliomas in the midline of the brain are considered part of the most lethal form of cancer.
No medical therapy has been shown to extend survival in H3K 27M mutant adult and pediatric glioma patients. Standard of care DIPG treatment (55Gy focal radiation fractionation for more than 6 weeks) was associated with an overall survival of 9-11 months. Adult H3K 27M gliomas are often treated with the same regimen as glioblastoma involving radiation with concomitant and sustained temozolomide (temozolomide). Despite the use in treating this newly defined disease in adults, the efficacy of this regimen in adult patients with mutant H3K 27M glioma has not been specifically evaluated.
The function of histones is mainly protein-DNA and protein-protein interactions; it does not act as an enzyme, which represents the majority of targeted cancer therapies (kinases, HDAC inhibitors, etc.). Thus, no therapy directly targets the mutant H3 protein itself (as is the case for mutant BRAF); in contrast, therapeutic efforts have focused on targeting characteristics of tumor cells with the H3K 27M mutation, such as their epigenetic and transcriptional dependence. Inhibition of proteins involved in epigenetics (such as histone deacetylase, histone demethylase, or bromodomain) has resulted in efficacy in preclinical models, however its ability to improve clinical outcomes has not been shown.
The main challenge for effective therapy of H3K 27M glioma is the need to penetrate the blood brain barrier, a rare feature of current cancer therapies. This is further enhanced by the location of these tumors in midline brain structures which have been shown to be more difficult to penetrate than other brain locations. The H3K 27M mutation also tended to occur in midline gliomas with dopamine present in the tumor environment and widespread DRD2 expression.
The lack of treatment for H3K 27M glioma has resulted in a substantial unmet medical need with respect to disease control, symptom relief, and survival. Patients with recurrent disease do not have any treatment regimen after radiation, but have proven survival benefits.
Disclosure of Invention
In one aspect, provided herein is a compound of formula (10):wherein R is1And R2Independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, and acyl. In one embodiment, when R1Is CH2At Ph, R2Is not CH2-(2-CH3-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2-(2-CH3-Ph) (ONC 201). In one embodiment, R 1Is CH2Ph and R2Is CH2- (2, 4-di F-Ph) (ONC 206). In one embodiment, R1Is CH2Ph and R2Is CH2-(4-CF3-Ph) (ONC 212). In one embodiment, R1Is CH2Ph and R2Is CH2- (3, 4-di F-Ph) (ONC 213). In one embodiment, R1Is CH2- (3, 4-di-Cl-Ph) and R2Is CH2-(4-CF3-Ph) (ONC 234). In one embodiment, R1Is CH2-3-thienyl and R2Is CH2-(4-CF3-Ph)(ONC236)。
In another aspect, provided herein is a method for treating or preventing cancer in a subject in need thereof, the method comprising: administering to said subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of compound (1)
Or a pharmaceutically acceptable salt thereof, wherein the cancer involves the midline structure of the brain and has a histone H3K27M mutation.
In another aspect, provided herein is a method for treating or preventing cancer in a subject in need thereof, the method comprising: administering to the subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (10) or an analog or pharmaceutically acceptable salt thereof, wherein the cancer has a histone H3 mutation.
In another aspect, provided herein is a method for treating or preventing cancer in a subject in need thereof, the method comprising: administering to the subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (10) or an analog or pharmaceutically acceptable salt thereof, wherein the cancer involves the midline structure of the brain.
Drawings
The foregoing summary, as well as the following detailed description of embodiments of the present invention, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.
In the drawings:
figure 1 antagonism of ONC201 at dopamine receptors (DRD1, DRD2S, DRD2L, DRD3, DRD4 and DRD 5).
FIG. 2 tumor type sensitivity collected from cancer drug sensitive Genome (GDSC) project cell lines. IC by mean estimation from cell viability assays performed 72 hours after treatment50The values determine the average sensitivity. The numbers above the bar indicate the number of cell lines per tumor type.
Figure 3 GBM cell lines with higher DRD2 or lower DRD5 expression responded more strongly to ONC 201. (A) Inhibition of the NCI60GBM cell line as a function of ONC201 concentration. (B) Log ONC201 GI per GBM cell line50(M) expression of
Figure 4 ONC206 and ONC212 showed anticancer efficacy in various tumor types in NCI60 cancer cell line panels. ONC203 is an inactive negative control.
Figure 5 bone cancer responded to ONC206 more strongly than ONC 201.
FIG. 6 Ewing's sarcoma is the subtype of bone cancer that responds most strongly to ONC 206.
FIG. 7 ONC206 has anti-cancer efficacy in the nanomolar range in 14 of the 16 Ewing sarcoma cell lines; it showed superior efficacy in all cell lines compared to ONC 201.
Fig. 8 leukemia responds stronger to ONC212 than ONC 201.
Figure 9. ONC212 shows anticancer efficacy in the nanomolar range in 55 leukemia cell lines regardless of subtype (superior efficacy compared to ONC 201).
Figure 10 anticancer efficacy of ONC212 in Acute Myeloid Leukemia (AML) cell line. (A) Cell viability of MV411 AML cells treated with ONC212 or cytarabine (cytarabine) was compared. (B) Cell viability of MOLM14, MV411 AML cells, MRC5 lung fibroblasts and Hs27a bone marrow cells treated with ONC212 were compared. (C) Viability of MOLM14 and MV411 AML cells treated with ONC212(250nM) for 4, 8, 24, 48, 72 and 96 hours.
FIG. 11 ONC212 in AML xenograft model (MV411 AML cells (5X 10) against ONC2016) Subcutaneous implantation into the flank of athymic nude mice). ONC212 and ONC201 were administered orally (PO) as indicated. Tumor volumes (a and B) and body weights (C) were measured on the indicated days (n ═ 10). Denotes p < 0.05 relative to vehicle.
FIG. 12 ONC206 in Ewing's sarcoma xenograft model (MHH-ES-1 Ewing's sarcoma cells (5X 10)6) Subcutaneous implantation into the flank of athymic nude mice). ONC206(PO) and methotrexate (IV) were administered on
Figure 13 ONC213 has similar in vitro anti-cancer efficacy as ONC212 in HCT116/RPMI8226 cancer cells, but the in vitro toxicity of ONC213 to normal cells was reduced compared to ONC 212.
Figure 14 immune induction was associated with tumor shrinkage in glioblastoma.
Fig. 15. a 74 year old female with recurrent H3K27M glioblastoma. An 8 week MRI of the first treatment showed complete disappearance of the tumor lesions.
Figure 16. a 10 year old girl with H3K27M diffuse endogenous pontine glioma improved facial paralysis and reduction of lesions after 16 doses.
Fig. 17. a 3 year old girl with H3K27M diffuse endogenous pontine glioma. MRI for the first 6 weeks of treatment showed stable tumor lesions.
Figure 18. progression free survival of patients with recurrent high grade glioma presented at baseline was determined by MRI prior to initiation of ONC201 therapy. Groups are divided into two groups: one group had a known H3K27M mutation (red curve) and the other group had a wild-type or unknown H3 state (blue curve).
Figure 19 waterfall of adult recurrent H3K 27M mutant glioma patients treated with ONC 201. The change in tumor size was calculated as the change at optimal treatment compared to baseline in the sum of the perpendicular diameter products of all measurable enhanced lesions. PD-disease progression according to RANO; SD-disease stabilization according to RANO; PR-partial response according to RANO; NE-an unassassassable response according to RANO (< 1cm multifocal lesions).
Fig. 20 (a) gadolinium enhanced MRI at baseline and 72 weeks after ONC201 onset for 2 lesions of patients with recurrent H3K 27M mutant thalamic midline glioma who received 625mg ONC201 once every three weeks. (B) The total tumor size relative to baseline over the duration of ONC201 administration is shown.
Figure 21 gadolinium enhanced MRI at baseline and 8 weeks (625 mg weekly) after ONC201 start in patients with recurrent H3K 27M mutant gliomas.
Figure 22 gadolinium enhanced MRI at baseline and 15 weeks (625 mg weekly) after ONC201 start in patients with recurrent H3K 27M mutant gliomas.
Detailed Description
Scientific and technical terms used herein are intended to have the meanings commonly understood by one of ordinary skill in the art. Such terms may be found and used in the context of various standard references, which illustratively include the following: sambrook and Russell, molecular cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press; 3 rd edition, 2001; authored by ausubel, manual in molecular biology (Short Protocols in molecular biology), manual in laboratory (Current Protocols); 5 th edition, 2002; alberts et al, Molecular Biology of the Cell, 4 th edition, Karan scientific Press (Garland), 2002; nelson and Cox, Principles of Biochemistry (Lehninger Principles of Biochemistry), 4 th edition, w.h. frieman corporation (w.h. freeman & Company), 2004; engelke, d.r., "RNA interference (RNAi): specific details of RNAi Technology (RNA Interference (RNAi): Nuts and bones of RNAi Technology), DNA Press, Inc., of Igwell, Pa (DNA Press LLC, Eagleville, Pa.), 2003; herdewijn, P. (editors), "oligonucleotide synthesis: methods and uses (Oligonucleotide Synthesis: Methods and Applications), Methods in Molecular Biology (Methods in Molecular Biology), Humana Press, 2004; nagy et al, mouse embryo manipulation: a Laboratory Manual (Manipulating the mouse Embryo: A Laboratory Manual), 3 rd edition, Cold spring harbor Laboratory Press; 2002, ISBN-10: 0879695919; kursad Turksen (ed), "embryonic stem cells: methods and protocols in molecular biology Methods (Methods and protocols in Methods Mol Biol.) 2002; 185, sumanax press; guidelines for Stem Cell Biology (Current Protocols in Stem Cell Biology), ISBN:9780470151808 and U.S. Pat. No. 8,673,923. The contents of each of the above references are incorporated herein by reference in their entirety.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. When the substituent is a keto group (i.e., ═ O), then 2 hydrogens on the atom are replaced. The keto substituent is not present on the aromatic moiety. A cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N).
In a variable (e.g. R)4) When a compound occurs more than one time in a constituent or formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown as being substituted with 0-3R4Partially substituted, the group may be optionally substituted with up to three R4Is partially substituted and R4Independently at each occurrence selected from R4The definition of (1). Moreover, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When an atomic or chemical moiety is followed by a numerical range of the subscript (e.g., C)1-6) It is to be understood that this encompasses each and every number within the stated range as well as all intermediate ranges. For example, "C1-6Alkyl "is meant to encompass alkyl groups having 1, 2, 3, 4, 5, 6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.
"alkyl" includes branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. E.g. C1-6The alkyl group containing C1、C2、C3、C4、C5And C6An alkyl group. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl. In some cases, the linear or branched alkyl group has six or fewer carbon atoms in its backbone (e.g., C for linear chain)1-C6For the side chain is C3-C6) (ii) a In other cases, the straight or branched chain alkyl has four or fewer carbon atoms. Likewise, a cycloalkyl group can have three to eight ring structures in its ring structureCarbon atoms; in some cases, the cycloalkyl group has five or six carbons in the ring structure. Most preferred is C1-6Alkyl radicals, in particular ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.
The term "substituted alkyl" means an alkyl group substituted with: selected from halogen, -OH, alkoxy, -NH2、-N(CH3)2-C (═ O) OH, trifluoromethyl, -C.ident.N, -C (═ O) O (C)1-C4) Alkyl, -C (═ O) NH2、-SO2NH2、-C(＝NH)NH2and-NO2One, two or three substituents of (a); preferably containing a halogen atom selected from the group consisting of-OH, alkoxy, -NH 2Trifluoromethyl, -N (CH)3)2and-C (═ O) OH, more preferably one or two substituents selected from halogen, alkoxy and-OH. Examples of substituted alkyl groups include 2, 2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.
Unless the number of carbons is otherwise specified, "lower alkyl" is an alkyl group having from one to six carbon atoms, preferably one to four carbon atoms, in its main chain. The chain length of "lower alkenyl" and "lower alkynyl" is 2-6 carbon atoms, and preferably 2-4 carbon atoms.
"alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" encompasses straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl groups (e.g., alicyclic) (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl-or alkenyl-substituted cycloalkenyl groups, and cycloalkyl-or cycloalkenyl-substituted alkenyl groups. In some cases, a straight or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C for straight chain) 2-C6For the side chain is C3-C6). Likewise, cycloalkenyl groups can have three to eight carbon atoms in their ring structure; in some cases, cycloalkenyl groups have five or six in the ring structureAnd (3) carbon. The term "C2-C6"and" C3-C6"comprises alkenyl groups containing two to six carbon atoms and three to six carbon atoms, respectively.
"alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched chain alkynyl, and cycloalkyl-or cycloalkenyl-substituted alkynyl. In some cases, a straight or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C for a straight chain)2-C6For the side chain is C3-C6). The term "C2-C6"and" C3-C6"comprises alkynyl groups containing two to six carbon atoms and three to six carbon atoms, respectively.
The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each of the atoms forming the ring (i.e., the backbone atoms) is a carbon atom. In some cases, the cycloalkyl group is saturated or partially unsaturated. In other cases, the cycloalkyl is fused to an aromatic ring. Cycloalkyl groups comprise groups having 3 to 10 ring atoms. Examples of cycloalkyl groups include, but are not limited to, the following moieties:
Monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl groups include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyl groups include adamantane and norbornane. The term cycloalkyl includes "unsaturated non-aromatic carbocyclic group" or "non-aromatic unsaturated carbocyclic group", both referring to a non-aromatic carbocyclic ring as defined herein, which contains at least one carbon-carbon double bond or one carbon-carbon triple bond.
The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. Exemplary cycloalkylalkyl groups include cyclopropylalkyl, cyclohexylalkyl.
The term "heterocycloalkyl" refers to a non-aromatic heterocyclic ring in which one or more of the ring-forming atoms is a heteroatom such as O, N or an S atom. Heterocycloalkyl includes monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) ring systems as well as spiro rings. Examples of heterocycloalkyl groups include morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodiocene, benzo-1, 4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, and imidazolidinyl. Moieties having one or more aromatic rings fused (i.e., having a common bond) to a non-aromatic heterocyclic ring may also be included in the definition of heterocycloalkyl, e.g., quinolinyl, isoquinolinyl, and benzo derivatives of heterocyclic rings. Heterocycloalkyl groups having one or more fused aromatic rings are attached through aromatic or non-aromatic moieties. Also included in the definition of heterocycloalkyl are moieties in which one or more ring-forming atoms may be substituted with 1 or 2 oxo or thioionic groups. In some cases, heterocycloalkyl groups have from 1 to about 20 carbon atoms, and in further cases from about 3 to about 20 carbon atoms. In some cases, the heterocycloalkyl group contains from 3 to about 20, from 3 to about 14, from 3 to about 7, or from 5 to 6 ring-forming atoms. In some cases, the heterocycloalkyl group contains 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some cases, the heterocycloalkyl group contains from 0 to 3 double bonds. In some cases, the heterocycloalkyl group contains from 0 to 2 triple bonds.
The term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group. Exemplary heterocycloalkylalkyl groups include morpholinylalkyl and piperazinylalkyl.
The term "aryl" refers to an aromatic hydrocarbon, such as phenyl, naphthyl, anthryl, phenanthryl, that is monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). In some cases, the aryl group has 6 to 20 carbon atoms.
The term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary arylalkyl groups include benzyl and phenethyl.
The term "heteroaryl" refers to an aromatic heterocyclic ring having at least one heteroatom ring member (e.g., an O, S or N atom). Heteroaryl groups comprise monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) systems. The ring-forming N atoms in the heteroaryl group can also be oxidized to form an N-oxo moiety. Examples of heteroaryl groups include pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl. In some cases, heteroaryl groups have from 1 to about 20 carbon atoms, and in some cases from about 3 to 20 carbon atoms. In some cases, a heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some cases, a heteroaryl group contains 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
"heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. An example of heteroarylalkyl is pyridylmethyl.
The term "halo" or "halogen" refers to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom; preferably, F, Cl or Br; more preferably, F or Cl. The term "perhalogenated" refers to a moiety wherein all hydrogens are replaced with halogens. The term "haloalkyl" refers to an alkyl group having a halogen replacing a hydrogen on one or more carbons of the hydrocarbon backbone. C1-C6Haloalkyl comprises a straight or branched chain alkyl having six or less backbone carbon atoms and halogen replaces a hydrogen on one or more backbone carbons.
The term "alkoxy (alkoxy or alkxyl)" encompasses substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently bonded to an oxygen atom. C1-C6Alkoxy refers to a moiety having six or fewer carbon atoms in the hydrocarbon backbone. Examples of alkoxy (alkoxy group or alkoxy radial) include methoxy, ethoxy, isopropoxy, propoxyButoxy and pentoxy. Is preferably (C)1-C3) Alkoxy, in particular ethoxy and methoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups.
The term "hydroxy" (hydroxy or hydroxyyl) includes moieties having-OH or-O –A group of (1).
The term "pharmaceutically acceptable salt" refers to a derivative of a compound that is modified by converting an existing acid or base moiety into its salt form. Non-limiting examples of pharmaceutically acceptable salts include mineral or organic acid salts of basic residues such as amines; such as alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found below: remington's Pharmaceutical sciences, 17 th edition, mark Publishing Company of Easton, PA (Mack Publishing Company, Easton, PA),1985, p.1418, Journal of Pharmaceutical sciences, 66,2(1977) and editions by p.stahl and c.wermuth, handbook of Pharmaceutical salts: properties, Selection, and Use (Handbook of pharmaceutical Salts: Properties, Selection and Use),
Examples of suitable inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, while examples of suitable organic acids include carboxylic, sulfonic (sulfoacid) or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, maleic acid, salicylic acid, trifluoroacetic acid, 3-aminosalicylic acid, ascorbic acid, pamoic acid, nicotinic acid, isonicotinic acid, oxalic acid, gluconic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-isethionic acid, ethane-1, 2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid. Examples of suitable inorganic bases include sodium hydroxide, potassium hydroxide and ammonia, while examples of suitable organic bases include amines, for example, tertiary amines, such as trimethylamine, triethylamine, pyridine, N-dimethylaniline, quinoline, isoquinoline, α -picoline, β -picoline, γ -picoline, quinaldine or pyrimidine.
The term "antibody" encompasses the structure of the native biological form that makes up the antibody. In most mammals, including humans and mice, this form is a tetramer and consists of two identical pairs of two immunoglobulin chains, each pair having one light chain and one heavy chain, each light chain including an immunoglobulin domain V LAnd CLAnd each heavy chain comprises an immunoglobulin domain VHC γ 1,
Based on the heavy chain constant domain amino acid sequence, the complete antibody can be assigned to different "classes". There are five major classes of intact antibodies (isotypes): IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into "subclasses," e.g., IgG1, IgG2, IgG3, IgG4, IgA, and
The term "antibody" or "antigen-binding fragment" refers to the complete molecule and functional fragments thereof, respectively, that can specifically interact with the desired target, such as Fab, scFv-Fc bivalent molecule, F (ab')2And Fv. In some cases, the antigen-binding fragment comprises:
(1) fab, monovalent antigen-binding fragments containing antibody molecules that can be produced by digesting whole antibodies with the enzyme papain to produce a complete light chain and a portion of one heavy chain;
(2) fab', fragments of an antibody molecule that can be obtained by treating the whole antibody with pepsin, followed by reduction to produce a portion of the complete light and heavy chains; obtaining two Fab' fragments per antibody molecule;
(3)(Fab')2fragments of an antibody, which may be obtained by treating the whole antibody with the enzyme pepsin without subsequent reduction; f (ab ')2 is a dimer of two Fab' fragments held together by two disulfide bonds;
(4) fv, a genetically engineered fragment containing the variable regions of the light and heavy chains expressed as two chains;
(5) single chain antibodies ("SCAs"), comprising a light chain variable region and a heavy chain variable region, genetically engineered molecules linked as genetically fused single chain molecules by suitable polypeptide linkers; and
(6) scFv-Fc, which is produced by fusing a single chain fv (scFv) with a hinge region (e.g., IgG) and an Fc region from an immunoglobulin (Ig).
In one embodiment, the antibodies provided herein are monoclonal antibodies. In one embodiment, an antigen-binding fragment provided herein is a single chain Fv (scFv), diabody, tandem scFv, scFv-Fc bivalent molecule, Fab ', Fv, F (ab')2Or antigen-binding scaffolds (e.g., affibodies, single antibodies, anti-transportins (anticalins), darpins, knottins (knottins)).
The term "binding" or grammatical equivalents refers to compositions that have an affinity for each other, either directly or indirectly. "specific binding" refers to selective binding between two molecules. For example, specific binding occurs between an antibody and an antigen. In general, when dissociation constant (K)D) Less than about 1X 10-5M or less than about 1X 10-6M or 1X 10-7M, specific binding can be distinguished from non-specific binding. Specific binding can be detected, for example, by ELISA, immunoprecipitation, co-precipitation, with or without chemical cross-linking, and two-hybrid assays. The use of appropriate controls allows for the discrimination of "specific" binding from "non-specific" binding. "affinity" is the strength of the binding interaction of two molecules (e.g., an antigen and its antibody), which is defined for antibodies and other molecules with more than one binding site as the strength of binding of a ligand at a given binding site. Although the non-covalent attachment of a ligand to an antibody or other molecule is generally not as strong as the covalent attachment, "high affinity" ligands are generally greater than 10 4M-1(generally 10)5-1011M-1) Affinity constant (K) ofa) Binding to antibodies or other molecules; as determined by inhibition ELISA or by equivalent techniques such as Scatchard plots (Scatchard plots) or as KaK of reciprocal of (1)dEquivalent affinity determined by dissociation constant.
With respect to binding, inhibiting, stimulating, or modulating, the term "selective" means preferential binding, inhibition, stimulation, or modulation of a first activity relative to a second activity, respectively (e.g., preferential binding of one receptor to another receptor; preferential inhibition relative to the other receptor; or preferential inhibition of a mutant relative to the wild-type, or vice versa). In some cases, the binding is more selective than two-fold, more than five-fold, more than ten-fold, more than fifty-fold, more than 100-fold, or more than 1000-fold over the desired molecular target or pathway relative to the undesired molecular target or pathway. In some cases, under the same conditions, a compound will bind to a first molecular target or affect a pathway at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to a second target or pathway. It will be appreciated that in a preferred embodiment, with respect to the D1-like family of dopamine receptors or members thereof, binding to the D2-like family of dopamine receptors or members thereof will be selective in one of the aforementioned amounts. The in vitro or in vivo activity of a molecular target or pathway may be measured by any suitable reproducible method.
The term "modulate" refers to "stimulating" or "inhibiting" the activity of a molecular target or pathway. For example, a composition modulates the activity of a molecular target or pathway if the activity is stimulated or inhibited by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99% or more by the composition relative to the activity of the molecular target or pathway under the same conditions but in the absence of the composition. In another example, a composition modulates the activity of a molecular target or pathway if the activity is stimulated or inhibited by at least 2 fold, at least 5 fold, at least 10 fold, at least 20 fold, at least 50 fold, at least 100 fold relative to the activity of the target or pathway under the same conditions but in the absence of the composition. The activity of a molecular target or pathway can be measured by any reproducible method. For example, the activity of a molecular target or pathway can be measured in vitro or in vivo by suitable assays known in the art for measuring activity. Control samples (not treated with the composition) may be assigned a relative activity value of 100%.
In one embodiment, the antibody, antigen-binding fragment, or affinity tag has a K between 0.1nM and 10mM, 0.1nM and 1mM, or in the range of 0.1nMDBinds to its target. In one embodiment, it is administered at a K of 0.1-2nM, 0.1-1nM, 0.05-1nM, 0.1-0.5nM or 0.1-0.2nMDBinds to its target. In one embodiment, it binds directly to its target. In one embodiment, the peptide binds its target indirectly, e.g., the second antibody binds to the antibody bound to the target.
The phrase "label" refers to a compound or composition that is directly or indirectly conjugated or fused to an agent, such as a nucleic acid probe or antibody, and facilitates detection of the agent conjugated or fused thereto. The label may be detectable by itself (e.g., a radioisotope or fluorescent label), or, in the case of an enzymatic label, may catalyze chemical alteration of a detectable substrate compound or composition.
The term "probe" refers to a synthetically or biologically produced nucleic acid containing a specific nucleotide sequence that hybridizes to a target nucleic acid sequence under stringent conditions. The terms "label probe", "nucleic acid probe operably linked to a detectable label" or "nucleic acid strand operably linked to a detectable label" refer to a probe prepared with a marker group or "detectable label" for detection. The marker group is attached internally at the 5 'end, the 3' end, or a combination thereof. In other words, one probe may be linked to multiple markers. Preferred groups are recognition markers, such as fluorophores. The labeled probe may also include a plurality of different nucleic acid sequences each labeled with one or more markers. Each marker may be the same or different. It may be beneficial to label different probes (e.g., nucleic acid sequences) with different markers each. This can be achieved by having a single distinguishable group on each probe. For example, probe a is attached to group X and probe B is attached to group Y. Alternatively, probe A is attached to groups X and Y, and probe B is attached to groups Z and W. Alternatively, probe A is attached to groups X and Y, and probe B is attached to groups Y and Z. All of the probes "a" and "B" above will be distinguishable and uniquely labeled.
By "tissue sample" is meant a collection of similar cells obtained from the tissue of a subject or patient, preferably containing nucleated cells with chromosomal material. The four major human tissues are (1) the epithelium; (2) connective tissue, including blood vessels, bone and cartilage; (3) muscle tissue; and (4) neural tissue. The tissue sample source may be solid tissue, such as from a fresh, frozen and/or preserved organ or tissue sample or biopsy or aspirate; blood or blood components; body fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid or interstitial fluid; cells from a subject at a time of pregnancy or development. The tissue sample may also be primary or cultured cells or cell lines. Tissue samples may contain compounds that are not naturally intermixed with tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, or antibiotics. By tissue sample "section" is meant a single portion of a tissue sample or a sheet of a tissue sample, e.g., a tissue or cell sheet cut from a tissue sample. Multiple sections of a tissue sample may be taken and analyzed. By "cell line" is meant a permanently established cell culture that will proliferate upon administration of appropriate fresh medium and space.
Detection method
In various aspects, provided herein are methods of detecting or measuring a target receptor (e.g., a dopamine receptor or GPCR) in a biological sample. The target is detected by contacting the sample with a target detection reagent (e.g., an antibody or fragment thereof) and a labeling reagent. The presence or absence of the target is detected by the presence or absence of the labeling agent. In some cases, the sample is contacted with the target detector and the labeling agent simultaneously, e.g., the detection agent is a first antibody and the labeling agent is a fluorescent dye conjugated thereto. Alternatively, the biological sample is contacted with the target detector and the labeling reagent sequentially, e.g., the detection reagent is a first antibody and the labeling reagent comprises a second antibody. For example, the sample is incubated with the detection reagent (and, in some cases, the labeling reagent) under conditions that allow for the formation of a complex between the detection reagent (and the labeling reagent) and the target. After the complex is formed, the sample is optionally washed one or more times to remove unbound detection reagent (and labeled reagent). When the sample is further contacted with a labeled reagent that specifically binds to the detection reagent that binds to the target, the sample can optionally be washed one or more times to remove unbound labeled reagent. The presence or absence of the target in the sample is then determined by detecting the labeled reagent.
The methods described herein provide for the detection of multiple targets in a sample. The biological sample is contacted with additional detection reagents using the methods described, and then contacted with additional labeling reagents specific for the additional detection reagents to identify the plurality of targets.
The detection moiety (i.e., detectable label) is a substance used to facilitate target recognition and/or quantification. The detection moiety is either directly observed or measured or indirectly observed or measured. Non-limiting examples of detection moieties include radioactive labels that can be measured with a radiation counting device; a pigment, dye or other chromogen that can be visually observed or measured with a spectrophotometer; a spin label that can be measured with a spin label analyzer; and a fluorescent moiety, wherein the output signal is generated by excitation of the appropriate molecular adduct and can be visualized by optical excitation absorbed by the dye or can be measured with a standard fluorometer or imaging system. The detection moiety may be a luminescent substance, such as a phosphor and a fluorophore; a bioluminescent material; a chemiluminescent substance, wherein the output signal is generated by chemical modification of the signal compound; a metal-containing substance; or an enzyme, wherein enzyme-dependent secondary generation of a signal occurs, such as the formation of a colored product from a colorless substrate. The detection moiety may also be in the form of a chemical or biochemical or inert particle comprising colloidal gold, microspheres, quantum dots, or inorganic crystals such as nanocrystals or phosphors. The term "detection moiety" or "detectable label" may also refer to a "tag" or hapten that can be selectively bound to a labeling molecule such that when the labeling molecule is subsequently added, a detectable signal is generated using the labeling molecule. For example, biotin, iminobiotin or desthiobiotin may be used as a label and then avidin or streptavidin conjugate of horseradish peroxidase (HRP) is used to bind to the label, and then the presence of HRP is detected using a chromogenic substrate (e.g., tetramethylbenzidine) or a fluorescent substrate (such as Amplex Red or Amplex Gold (Molecular Probes, Inc.)). Similarly, the tag may be a hapten or antigen (e.g., digoxigenin), and may be bound to the tag using an enzymatically, fluorescently, or radioactively labeled antibody. Many labels are known to those skilled in the art and non-limiting examples include particles, fluorescent dyes, haptens, enzymes and their chromogenic, fluorogenic and chemiluminescent substrates.
Fluorophores are chemical groups that exhibit an absorption maximum above 280nm and retain their spectral properties when covalently linked in a labeling reagent. Fluorophores include pyrene, anthracene, naphthalene, acridine, stilbene, indole or benzindole, oxazole or benzoxazole, thiazole or benzothiazole, porphyrin, cyanine, perylene, 4-amino-7-nitrobenz-2-oxa-1, 3-oxadiazole (NBD), carbocyanine, carbostyryl, salicylate, anthranilate, azure, pyridine, quinoline, borapolyazaindoline (borapolyazaindacene), xanthene, oxazine or benzoxazine, carbazepine, fluorenone (phenalenone), coumarin, benzofuran and benzofluorenone (benzaphenalenone), and derivatives thereof. Oxazines include resorufin, aminooxazinones, diaminooxazines, and their benzo-substituted analogs.
For xanthene fluorophores, the fluorophore may be fluorescein, rhodol (rhodol), or rhodamine (rhodamine). Fluorescein includes benzo or dibenzo fluorescein (benzo-or dibenzo fluorescein), heminaphthofluorescein (seminaphthofluorescein), or naphthofluorescein (naphthofluorescein). Similarly, p-methylaminophenols contain heminaphthol rhodamine fluorescences (seminaphthorrhodafluors). Alternatively, the fluorophore is a xanthene bound by a single covalent bond at the 9 position of the xanthene. Preferred xanthenes comprise derivatives of 3H-xanthen-6-ol-3-one, 6-amino-3H-xanthen-3-one or 6-amino-3H-xanthen-3-imine. Fluorophores include xanthenes (p-methylaminophenol, rhodamine, fluorescein and its derivatives), coumarins, cyanines, pyrenes, oxazines and boranophenylazaindoles. In addition, the fluorophore may be sulfonated xanthene, fluorinated xanthene, sulfonated coumarin, fluorinated coumarin, and sulfonated cyanine. The choice of fluorophore in the labeling reagent will determine the absorption and fluorescence emission properties of the labeling reagent. The physical properties of fluorophore labels, which can be used to distinguish one fluorophore from another, include spectral characteristics (absorption, emission and stokes shift), fluorescence intensity, lifetime, polarization and photobleaching rate.
Typically, the fluorophore contains one or more aromatic or heteroaromatic rings optionally substituted with one or more substituents comprising halogen, nitro, cyano, alkyl, perfluoroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, arylalkyl, acyl, aryl or heteroaryl ring systems, benzo, or other substituents known in the art to be commonly found on fluorophores.
Preferably, the detection moiety is a fluorescent dye. Fluorescent dyes include, for example, fluorescein, rhodamine, Texas Red (Texas Red), Cy2, Cy3, Cy5, Cy0, Cy0.5, Cy1, Cy1.5, Cy3.5, Cy7, VECTOR Red, ELFTM(enzyme-labeled fluorescence), FluorX, calcein-AM, CryptoFLUORTM' S, orange (42kDa), orange (35kDa), gold (31kDa), red (42kDa), deep red (40kDa), BHMP, BHDMAP, Br-Oregon, Lucifer Yellow, Alexa dye family (Alexa dye family), N- (6- (7-nitrobenz-2-oxa-1, 3-oxadiazol-4-yl) amino) hexanoyl) (NBD), BODIPYTMBoromethylenedipyrromethene difluoride (borondipyrrole difluoride), Oregon Green (Oregon Green), MITOTACTERKERTMRed, DiOC7(3), DiIC18, phycoerythrin, phycobiliprotein BPE (240kDa) RPE (240kDa) CPC (264kDa) APC (104kDa), Spectrum Blue (Spectrum Blue), Spectrum water (Spectrum Aqua), Spectrum Green (Spectrum Green), Spectrum Gold (Spectrum Gold), Spectrum orange (Spectrum orange), Spectrum Red (Spectrum Red), NADH, NADPH, FAD, Infrared (IR) dyes, Cyclic GDP-Ribose (cGDDPR), Calcofluor White, tyrosine and tryptophan. Many fluorophores can also act as chromophores and thus these fluorophores are also preferred chromophores.
In addition to fluorophores, enzymes have also found use as detectable moieties. An enzyme is a desirable detectable moiety because amplification of the detectable signal can be achieved, resulting in increased assay sensitivity. The enzyme does not itself produce a detectable response, but when contacted with an appropriate substrate, the enzyme will break down the substrate, allowing the converted substrate to produce a fluorescent, colorimetric or luminescent signal. Because one enzyme on the labeling reagent will cause multiple substrates to be converted into a detectable signal, the enzyme will amplify the detectable signal. This is advantageous if low amounts of target are present in the sample or no fluorophore is present which produces a signal comparable to or stronger than the enzyme. However, fluorophores are preferred because they do not require additional assay steps and therefore reduce the total time to complete the assay. The enzyme substrate is selected to produce a preferred measurable product, e.g., colorimetric, fluorescent or chemiluminescent. Such substrates are widely used in the art.
Preferred colorimetric or fluorescent substrates and enzymes use a combination of an oxidoreductase such as horseradish peroxidase and a substrate such as 3,3' -Diaminobenzidine (DAB) and 3-amino-9-ethylcarbazole-e (aec), which produce distinct colors (brown and red, respectively). Other non-limiting examples of colorimetric oxidoreductase substrates that produce detectable products include: 2, 2-azino-bis (3-ethylbenzothiazol-quinoline-6-sulfonic Acid) (ABTS), o-phenylenediamine (OPD), 3', 5, 5' -Tetramethylbenzidine (TMB), o-dianisidine, 5-aminosalicylic acid, 4-chloro-1-naphthol. Non-limiting examples of fluorogenic substrates include: homovanillic acid or 4-hydroxy-3-methoxyphenylacetic acid, reduced phenoxazines and reduced benzothiazines (including Amplexe Red reagent and its variants), and reduced dihydroxanthenes (including dihydrofluorescein and dihydrorhodamine including dihydrorhodamine 123). Peroxidase substrates which are tyramine-based represent a class of peroxidase substrates which may be inherently detectable prior to enzyme action but which are "fixed in place" by the action of peroxidase in a process described as Tyramine Signal Amplification (TSA). These substrates are widely used to label targets in cell, tissue or array samples for subsequent detection by microscopy, flow cytometry, optical scanning and fluorimetry.
Additional colorimetric substrates (fluorescent substrates in some cases) and enzymes a phosphatase (e.g., acid phosphatase, alkaline phosphatase, or a recombinant version of such a phosphatase) is used in combination with a colorimetric substrate (e.g., 5-bromo-6-chloro-3-indolyl phosphate (BCIP), 6-chloro-3-indolyl phosphate, 5-bromo-6-chloro-3-indolyl phosphate, p-nitrophenyl phosphate, or o-nitrophenyl phosphate) or with a fluorescent substrate (e.g., 4-methylumbelliferyl phosphate, 6, 8-difluoro-7-hydroxy 4-methylcoumarin phosphate (DiFMUP) fluorescein diphosphate, 3-0-methylfluorescein phosphate, resorufin phosphate, 9H- (1, 3-dichloro-9, 9-dimethylacridin-2-one-7-yl) phosphate (DDAO phosphate) or ELF 97, ELF 39 or related phosphates).
Glycosidases, in particular beta-galactosidase, beta-glucuronidase and beta-glucosidase are other suitable enzymes. Suitable colorimetric substrates comprise: 5-bromo 4-chloro-3-indolyl beta-D-galactopyranoside (X-gal) and similar indolyl galactosides, glucosides and glucuronides, o-nitrophenyl beta-D-galactopyranoside (ONPG) and p-nitrophenyl beta-D-galactopyranoside. Preferred substrates include resorufin beta-D-galactopyranoside, Fluorescein Digalactoside (FDG), fluorescein digluconate and structural variants thereof, 4-methylumbelliferyl beta-D-galactopyranoside, carboxyumbelliferyl beta-D-galactopyranoside and fluorinated coumarin beta-D-galactopyranoside. Other enzymes include hydrolases, e.g., cholinesterase and peptidase; oxidases, for example, glucose oxidase; and cytochrome oxidases and reductases for known suitable substrates.
Enzymes and their chemiluminescent-producing substrates are preferred for some assays. These include, for example, native and recombinant luciferases and aequorin. For luciferase or aequorin, exemplary substrates are luciferin, ATP, Ca for phosphatases, glycosidases, and oxidases++And coelenterazine chemiluminescent substrates, such as substrates containing stable dioxetanes, luminol, isoluminol, and acridinium esters are useful.
In addition to enzymes, haptens such as biotin are useful detectable moieties. Biotin is in an enzyme system that can further amplify the detectable signal and can serve as a tag in affinity chromatography for separation purposes. For detection, an enzyme conjugate with affinity for biotin, such as avidin-HRP, is used. Then, a peroxidase substrate is added to generate a detectable signal. Haptens also include hormones, naturally occurring and synthetic drugs, contaminants, allergens, effector molecules, growth factors, chemokines, cytokines, lymphokines, amino acids, peptides, chemical intermediates, or nucleotides.
In some cases, the detectable moiety is a fluorescent protein. For example, it comprises Green Fluorescent Protein (GFP), phycobiliprotein and its derivatives, luciferase or aequorin. Fluorescent proteins, particularly phycobiliproteins, are particularly useful for creating tandem dye-labeled labeling reagents. Tandem dyes include fluorescent proteins and fluorophores to obtain a larger stokes shift that is far from the absorption spectrum of the fluorescent protein. This is particularly advantageous for detecting low amounts of target in samples that maximally optimize the emitted fluorescence, in other words, the fluorescent protein hardly or even completely no longer absorbs the emitted light. The fluorescent protein and fluorophore act as an energy transfer pair, wherein the fluorescent protein emits a wavelength that the fluorophore absorbs, and then the fluorophore emits a wavelength that is farther away from the fluorescent protein than can be obtained with the fluorescent protein alone. Particularly useful combinations are phycobiliproteins and sulforhodamine fluorophores, sulfonated cyanine fluorophores; or a sulfonated xanthene derivative. Alternatively, the fluorophore is an energy donor and the fluorescent protein is an energy acceptor.
The method of visualizing the detection portion depends on the marker.
In some cases, the wavelength of light that produces a detectable optical response is selected to illuminate the sample, and the sample is observed with a device that detects the response. Devices for illuminating fluorescent compounds include hand-held ultraviolet lamps, mercury arc lamps, xenon lamps, lasers, and laser diodes. These illumination sources are optically integrated into a laser scanner, a fluorometer reader, or a standard or microfluorometer. The degree or location of the signal, as compared to a standard or expected response, is indicative of whether and to what extent the sample has a given characteristic or a desired target.
Detecting the optical response by visual inspection or using one of the following means: CCD cameras, video cameras, photographic films, laser scanning devices, fluorometers, photodiodes, quantum counters, epifluorescence microscopes, scanning microscopes, flow cytometers, fluorescence microplate readers, or devices such as photomultiplier tubes for amplifying signals. When examining a sample using a flow cytometer, the examination of the sample optionally comprises sorting portions of the sample according to their fluorescent response.
When an indirectly detectable label is used, then illumination typically involves the addition of a reagent to produce a detectable signal such as a colorimetric enzyme substrate. Radioisotopes are also considered to be indirectly detectable in the event that no additional reagents are needed, but rather the radioisotope is exposed to X-ray film or other mechanisms to record and measure signals. This is true for some of the chemiluminescent signals observed after exposure to film.
Onc201 (compound (1)), salts thereof and synthesis thereof
Provided herein are ONC201 (Compound (1))Analogs thereof and pharmaceutically acceptable salts thereof, and synthesis thereof. In vitro models, animal models and human clinical trials, ONC201 has broad anticancer activity, low toxicity (including few side effects, if any), low genotoxicity and high bioavailability including oral administration. These features make the ONC201 and various analogs well suited for a variety of applications. The ONC201 can be synthesized as shown in scheme 1.
Scheme 1
Synthesis of ONC201 dihydrochloride starts with the commercially available intermediate N-benzyl-3-carbomethoxy-4-piperidone hydrochloride, compound (3). In one embodiment, compound (3) (step 1) is neutralized with a base to yield compound (4), the free base. For example, compound (3) is neutralized with an inorganic base to give compound (4). Alternatively, it is neutralized with an organic base to give compound (4). In one embodiment, compound (3) is neutralized in the presence of an alcohol (e.g., n-butanol). In one embodiment, compound (3) is neutralized in the presence of at least one organic solvent (e.g., n-butanol, ethyl acetate, or both). In one embodiment, the reaction is carried out in the presence of a base and at least one organic solvent (e.g., NaHCO) 3And n-butanol) is neutralized. In one example, in n-butanol and triethylamine (Et)3N) is neutralized with a compound (3).
In one embodiment, the synthesis comprises reacting compounds (4) and (5) (step 2) to produce intermediate compound (1). In one embodiment,
In one embodiment, ONC201 dihydrochloride is synthesized (step 3). In one embodiment, step 3 comprises treating ONC201 with dioxane comprising HCl. In one embodiment, step 3 comprises treating ONC201 with 4N HCl in dioxane. In one embodiment, the synthesis optionally comprises recrystallizing ONC201 disalt. Preferably, ONC201 dihydrochloride is synthesized as shown in
TNF-related apoptosis-inducing ligand ("TRAIL")
TRAIL protein can be assayed in a sample obtained from a subject to detect TRAIL expression induced by the compounds described herein and salts thereof. Immunoassays including enzyme linked immunosorbent assays (ELISA), flow cytometry, enzyme linked immunosorbent assays (ELIFA), immunoblotting, immunoprecipitation, Fluorescent Immunoassays (FIA), immunohistochemistry, immunocytochemistry, Luminescent Immunoassays (LIA), and radioimmunoassays can be used. Qualitative and/or quantitative results may be obtained. Suitable methods for qualitative and quantitative determination are described in standard references, including Harlow and Lane, antibodies: a Laboratory Manual (Antibodies: A Laboratory Manual), Cold spring harbor Laboratory Press, 1988; breitling and Diibel, "Recombinant Antibodies (Recombinant Antibodies"), John Wiley father publishing company, N.Y. (John Wiley & Sons, New York), 1999; zola, monoclonal antibody: preparation and Use of Monoclonal Antibodies and engineered Antibody Derivatives (Monoclonal Antibodies: Preparation and Use of Monoclonal Antibodies and engineered Antibody Derivatives), basic: from background to Bench (Basics: From background to Bench), bioscience publishing company (BIOS Scientific Publishers), 2000; b.k.c.lo, < antibody engineering: methods and Protocols (antibodies Engineering: Methods and Protocols), "Methods in molecular biology", hama press, 2003; authored by Ausubel et al, a guide to molecular biology experiments, a guide to laboratories, Wiley publishing corporation (2002); klussman editors, < aptamer manual: functional Oligonucleotides and Their uses (the Aptamer Handbook: Functional Oligonucleotides and the same Applications), Willi publishing company, 2006; ormerod, m.g., flow cytometry: practical methods (Flow Cytometry: a practical laboratory), Oxford University Press, 2000; givan, a.l., "flow cytometry: first principles (Flow Cytometry, first principles), Wiley publishing company, New York, 2001; gorczyca, w., "flow cytometry in oncology hematology: morphology-correlation of immunophenotype (Flowcytometry in immunological-immunophenotyping), Taylor and Francis publishing group (Taylor & Francis), 2006; crowther, j.r., "The ELISA guide book (molecular biology methods)," angle of refraction, "hamana press, 2000; wild, d., (The Immunoassay Handbook), 3 rd edition, eisweil Science publishers (Elsevier Science), 2005; and Sambrook and Russell, molecular cloning: a laboratory Manual, Cold spring harbor laboratory Press, 3 rd edition, 2001.
Assays for analyzing TRAIL of a sample to detect the effect of a pharmaceutical composition are described in US 8,673,923, which is incorporated herein by reference in its entirety.
In one embodiment, the subject is monitored using a TRAIL assay. For example, samples are obtained from a subject before treatment with a pharmaceutical formulation and one or more times during and/or after treatment to assess the effect of the treatment. In another example, samples are obtained from a subject at various times to assess the course or course of a disease or cure. In one embodiment, death receptors from circulating tumor cells are assayed to see if the treatment described herein increases the number or type of death receptors.
Cancers treated using the methods and compositions described herein are characterized by abnormal cell proliferation, including pre-neoplastic hyperproliferation, carcinoma in situ, tumors, and metastases. The methods and compositions described herein can be used for prophylaxis and to ameliorate cancer signs or symptoms. The "treatment" of cancer in a subject comprises: preventing, inhibiting, or ameliorating cancer in a subject, such as slowing cancer progression or reducing or ameliorating signs or symptoms of cancer. Examples of cancers treated using the methods and compositions described herein include breast cancer, CNS cancer, colon cancer, ovarian cancer, prostate cancer, leukemia, lung cancer, and lymphoma.
Compounds of formula (10) and salts thereof
In one aspect, provided herein are compounds and salts of formula (10) and methods for their preparation. It will be understood by those skilled in the art that the general principles and concepts described herein in connection with ONC201 (compound (1)) and salts thereof, including those related to methods and pharmaceutical compositions, apply in an equivalent manner to the compounds of formula (10) and salts thereof.
In one embodiment, provided herein is a compound of formula (10):wherein R is1And R2Independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, and acyl. In one embodiment, R1Is CH2Ph and R2Is CH2-(2-CH3-Ph) (ONC 201). In one embodiment, R1Is CH2Ph and R2Is CH2- (2, 4-di F-Ph) (ONC 206). In one embodiment, R1Is CH2Ph and R2Is CH2-(4-CF3-Ph) (ONC 212). In one embodiment, R1Is CH2Ph and R2Is CH2- (3, 4-di F-Ph) (ONC 213). In one embodiment，R1Is CH2- (3, 4-di-Cl-Ph) and R2Is CH2-(4-CF3-Ph) (ONC 234). In one embodiment, R1Is CH2-3-thienyl and R2Is CH 2-(4-CF3-Ph)(ONC236)。
In one embodiment, R1And R2Independently selected from H, C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazine, C1-4Alkylthienyl, C1-4Alkyl pyridyl radical, C1-4Alkyl isoxazolidinyl, C1-4Alkyl morpholinyl, C1-4Alkylthiazolyl and C1-4Alkyl pyrazinyl radical, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazine, C1-4Alkylthienyl, C1-4Alkyl pyridyl radical, C1-4Alkyl isoxazolidinyl, C1-4Alkylthiazolyl, C1-4Alkyl morpholinyl and C1-4Alkyl pyrazinyl optionally substituted by C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, R1And/or R2Is a substituted or unsubstituted arylalkyl or heteroarylalkyl group. In one embodiment, heteroarylalkyl is selected from C1-4Alkyl pyrrolyl, C1-4Alkyl furyl group, C1-4Alkyl pyridyl radical, C1-4Alkyl-1, 2, 4-thiadiazolyl, C1-4Alkylthienyl, C1-4Alkyl isothiazolyl, C1-4Alkylimidazolyl group, C1-4Alkyl tetrazolyl, C1-4Alkyl pyrazinyl, C1-4Alkyl pyrimidinyl radical, C1-4Alkyl quinolyl, C1-4Alkyl pyrazolyl, C1-4Alkyl isoquinolinyl, C1-4Alkylthiophenyl radical, C1-4Alkylbenzothienyl, C1-4Alkyl isobenzofuranyl, C1-4Alkyl indolyl radical, C 1-4Alkyl purine radical, C1-4Alkyl carbazolyl group, C1-4Alkylbenzimidazolyl and C1-4An alkyl isoxazolyl group.
In one embodiment, R1And/or R2Is benzyl optionally substituted with one or more of the following substituents on the benzyl ring: x, -CH3、-NO2、-OCH3、-CN、-CXH2、-CX2H、C2-C4Alkyl, -CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3、-OCpH2p+1、-OCpX2p+1、ORm、SRm、NRmRn、NRmC(O)Rn、SORm、SO2Rm、C(O)RmAnd C (O) ORm；RmAnd RnIndependently selected from H or C1-C4An alkyl group; and wherein p is an integer from 2 to 20 and X is halogen, comprising F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl.
In one embodiment, R1Selected from H, CH3、CH2Ph、CH2-(4-CF3-Ph)、CH2-(4-F-Ph)、CH2-(4-Cl-Ph)、CH2-(OCH3-Ph)、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2- (3-thienyl), CH2-2-pyridyl, CH2-4-methyl-2-thiazolyl, CH2-2-pyrazinyl, CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2- (3, 4-di-Cl-Ph), CH2- (3, 4-di F-Ph), CH2- (3, 5-di F-Ph), CH2-((2-CH3)-Ph)、CH2CH (OH) Ph, (4-F-Ph) -4-oxobutyl, CH2CH2NHCOOC(CH3)3、CH2CH2CH2NH2And CD2C6D5. In one embodiment, R2Selected from H, CH3、CH2Ph、CH2-(4-CF3-Ph)、CH2-((2-Cl)-Ph)、CH2-((2-F)-Ph)、CH2- (2-thiophenes)Base), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2- (2, 4-dichloro-Ph), CH2- (3, 4-dichloro-Ph), CH2- (3, 4-di F-Ph), CH2- (3, 5-di F-Ph), CH2-((2-CH3)-Ph)、CH2(2-CH3,4-F-Ph)、CH2-((4-OCH3)-Ph)、CH2- (3-pyridyl), CH2- (3-isoxazolidinyl), CH2CH2- (4-morpholinyl), CH2-(2-F,4-CF3-Ph)、CH2CH(OH)Ph、(CH2)3CO-4F-Ph, (4-F-Ph) -4-oxobutyl, CH2CH2NHCOOC(CH3)3、CH2CH2CH2NH2And CD2C6D5。
In one embodiment, R 1Is H. In one embodiment, R1Is unsubstituted or substituted arylalkyl, e.g. benzyl (CH)2Ph) or phenethyl (CH)2CH2Ph). In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution.
In one embodiment, R2Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the arylalkyl group is selected from halo, CH3、CF3Or OCH3Is substituted with one or more substituents of (a). In one embodiment, R2Is a substituted or unsubstituted heterocycloalkylalkyl group, for example, a piperazinylalkyl group or a morpholinoalkyl group. In one embodiment, R2Is a substituted or unsubstituted heteroarylalkyl group, for example, pyridylmethyl or isoxazolidinylmethyl. In one embodiment, the heterocycloalkyl or heteroarylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo radicalsAnd (4) generation. In one embodiment, the heterocycloalkyl or heteroarylalkyl is selected from halo, CH3、CF3Or OCH3Is substituted with at least one substituent group.
In one embodiment, compound (10) has the structure of formula (80):wherein R isa1、Ra2、Ra3、Ra4、Ra5、Rb1、Rb2、Rb3、Rb4And Rb5Each independently selected from the group consisting of: H. x, -CH3、-NO2、-OCH3、-CN、-CXH2、-CX2H、C2-C4Alkyl, -CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3、-OCpH2p+1、-OCpX2p+1、ORm、SRm、NRmRn、NRmC(O)Rn、SORm、SO2Rm、C(O)RmAnd C (O) ORm；RmAnd RnIndependently selected from H or C1-C4An alkyl group; and wherein p is an integer from 2 to 20 and X is halogen.
In one embodiment, compound (10) has the structure of formula (90)Wherein R is2As defined above, and wherein Rb1、Rb2、Rb3、Rb4And Rb5Each independently selected from the group consisting of: H. x, -CH3、-NO2、-OCH3、-CN、-CXH2、-CX2H、C2-4Alkyl, -CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3、-OCpH2p+1、-OCpX2p+1、ORm、SRm、NRmRn、NRmC(O)Rn、SORm、SO2Rm、C(O)RmAnd C (O) ORm；RmAnd RnIndependently selected from H or C1-4An alkyl group; and wherein p is an integer from 2 to 20 and X is halogen.
In one embodiment, compound (10) has the structure of formula (40)
In one embodiment, compound (40) has the structure of compound (45):
In one embodiment, compound (10) has the structure of compound (50)
In one embodiment, compound (50) has the structure of compound (55):
In one embodiment, compound (10) has the structure of compound (60)
Scheme 3 illustrates the synthesis of compounds of formula (10):
the method comprises the following steps: NaH, dimethyl carbonate and toluene at 80 ℃ for 4 hours; 1N NaOH/CH2Cl2To convert to the free base and then heated in dioxane at 70 ℃; 1-Butanol/refluxing for 3-6 hours (dean-Stark trap) PPTS; d. dioxane, at 70 ℃; e. (ii) HCl in dioxane at-25 ℃ to RT to give HCl salt; f.Na2CO3DIEA, at 80 ℃; g.naOH/CH2Cl2To prepare the free base, then MeOH is refluxed for 3.5 hours
Scheme 3
The compound of formula (10) (isometrione) is synthesized starting from substituted piperidones, converted by reaction with substituted aminoimidazolines to give the core compound (10). There are two pathways, one of which is R1Substituents are present in piperidones (e.g., 68). In the route, (68) is acylated with dimethyl carbonate to form piperidone esters (69) at 80 ℃ using toluene containing sodium hydride. Reacting commercially available methylthioimidazoline HI salt (63) with amine-containing dioxane at 70 ℃ to give R as its HI salt2-substituted aminoimidazolines (64). (64) is reacted directly with 1-butanol containing piperidone ester (69) under reflux with removal of water by dean-Stark trap for 3-6 hours or more to give tricyclic compound (10). In one variant of this scheme, N-BOC protected piperidone (61) is converted to BOC protected compound (65) by the same method, which is treated with HCl-containing dioxane to remove the BOC group and then converted with 1N NaOH to the free base of (66), which is extracted with dichloromethane. Subsequent treatment (66) with a halide (67) or epoxide (70) affords the desired compound (10).
The crude product can be isolated by elution with dichloromethane, methanolBy column chromatography or by using acetonitrile TFA H2HPLC purification of O to yield the free base or TFA salt as the final product. Treatment of the free base with HCl in dioxane or lyophilized TFA salt yielded the product (10) as HCl or TFA salt. Alternatively, the free base may be treated with another mineral or organic acid to form other salts, typically selected from known pharmaceutically acceptable salts. The salt of compound (10) is usually a solid and examples have been crystallized from ethanol or other solvents to give high quality crystals. The tricyclic structure of compound (1) has been confirmed unambiguously by X-ray crystal structure and NMR.
The compounds described herein can be used with or without an aminoalkyl linker (e.g., compound (33)) to identify molecules (e.g., proteins) that interact with them in a cellular environment. Expression of these binding targets can be used to predict a response to (i.e., serve as a biomarker) emilianone or its analogs. These compounds can also be used to screen structurally unrelated molecules to identify drugs that are able to overcome target interactions with higher affinity, using competition assays known in the art. In addition, these molecules may have improved drug properties or allow additional applications by altering drug properties, including safety, efficacy, pharmacokinetics, biodistribution or metabolism.
Table 1: examples of the Compound having the formula (10)
Assessment of sensitivity and efficacy of treatment regimens
Measuring the expression, gene mutation or gene copy number of a dopamine receptor or other G protein-coupled receptor (GPCR) can be used to predict response or sensitivity to a treatment described herein or to identify a subject who is likely to respond to a treatment described herein, such as treatment with a compound of formula (10), a pharmaceutically acceptable salt thereof, or an analog thereof. In one aspect, provided herein are methods for identifying whether a subject having a condition is likely to respond to a treatment regimen described herein. In one embodiment, the method comprises (i) obtaining a biological sample from a subject; (ii) measuring the expression level of at least one dopamine receptor or GPCR in the sample; (iii) comparing the level measured in the sample with a level of a predetermined standard; and (iv) determining whether the subject is likely to respond to the treatment regimen based on a comparison of the level measured in the sample to a level of a predetermined standard. In one embodiment, the step of measuring the expression level in the sample comprises the steps of: (i) contacting the sample with an antibody or antigen-binding fragment that specifically binds to the receptor to form a complex of the antibody or antigen-binding fragment and the receptor; and (ii) measuring the amount of the complex. In one embodiment, the subject has or is at risk of having cancer. In one embodiment, the cancer is a neurooncologic disease. In one embodiment, the cancer is a neuroendocrine tumor. In one embodiment, the cancer is selected from the group consisting of: meningiomas, ependymomas, gliomas, neuroblastomas, and diffuse endogenous pontine gliomas. In one embodiment, the subject has or is at risk of having a psychiatric disorder. For example, the psychiatric disorder is selected from psychosis, bipolar disorder, and major depression. In one embodiment, the subject has or is at risk of having an infection such as a bacterial infection. In one embodiment, the infection is a gram positive bacterial infection. In one embodiment, the infection is a gram-negative bacterial infection. In one embodiment, the infection is an infection of a bacterium selected from the group consisting of: enterococcus faecium, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter bacteria. In one embodiment, the gram-positive bacterial infection is staphylococcus aureus. For example, the staphylococcal infection is a staphylococcus aureus infection (e.g., methicillin-resistant staphylococcus aureus (MRSA) infection). In one embodiment, the treatment regimen comprises administering an effective amount of a therapeutic agent, such as a compound of formula (10), a pharmaceutically acceptable salt thereof, or an analog thereof. In one embodiment, the dopamine receptor is from the D2-like family. In one embodiment, the dopamine receptor is DRD2, DRD3, or both. In one embodiment, the dopamine receptor is
In another aspect, provided herein are methods of assessing the effectiveness of a treatment regimen described herein, monitoring, or providing a prognosis for a subject having a condition. In one embodiment, the method comprises (i) obtaining a biological sample from a subject; (ii) measuring the expression level of at least one dopamine receptor or GPCR in the sample; (iii) comparing the level measured in the sample with a level of a predetermined standard; and (iv) determining the prognosis or whether the subject is responding to the treatment regimen based on a comparison of the level measured in the sample to the level of a predetermined standard. In one embodiment, the step of measuring the expression level of a dopamine receptor or GPCR in the sample comprises the steps of: (i) contacting the sample with an antibody or antigen-binding fragment that specifically binds to the receptor to form a complex of the antibody or antigen-binding fragment and the receptor; and (ii) measuring the amount of the complex. In one embodiment, the method comprises (i) obtaining a biological sample from a subject; (ii) measuring gene copy number or mutation of at least one dopamine receptor in the sample; (iii) comparing the gene copy number or the found mutation measured in the sample with a gene copy number or mutation of a predetermined standard; and (iv) determining whether the subject is responsive to the treatment regimen based on a comparison of the gene copy number or the mutation found in the sample to a gene copy number or mutation of a predetermined standard. In one embodiment, the subject has or is at risk of having cancer. In one embodiment, the cancer is a neurooncologic disease. In one embodiment, the cancer is a neuroendocrine tumor. In one embodiment, the cancer is selected from the group consisting of: meningiomas, ependymomas, gliomas, neuroblastomas, and diffuse endogenous pontine gliomas. In one embodiment, the subject has or is at risk of having a psychiatric disorder. For example, the psychiatric disorder is selected from psychosis, bipolar disorder, and major depression. In one embodiment, the subject has or is at risk of having an infection such as a bacterial infection. In one embodiment, the infection is a gram-negative bacterial infection. In one embodiment, the infection is a gram positive bacterial infection. In one embodiment, the infection is an infection of a bacterium selected from the group consisting of: enterococcus faecium, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter bacteria. In one embodiment, the gram-positive bacterial infection is staphylococcus aureus. For example, the staphylococcal infection is a staphylococcus aureus infection (e.g., methicillin-resistant staphylococcus aureus (MRSA) infection). In one embodiment, the treatment regimen comprises administering an effective amount of a therapeutic agent, e.g., a compound of formula (10), a pharmaceutically acceptable salt thereof, or an analog thereof. In one embodiment, the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD 3. In one embodiment, the dopamine receptor is from the D2-like family. In one embodiment, the dopamine receptor is from the D1-like family. In one embodiment, the dopamine receptor is DRD 1. In one embodiment, the dopamine receptor is
In one embodiment, the dopamine receptor is DRD5, the treatment regimen comprises administering an effective amount of a compound of formula (10) or a pharmaceutically acceptable salt thereof, and an increased level of DRD5 expression measured in the sample relative to a predetermined criterion indicates that the treatment regimen is effective or ineffective. In one embodiment, the dopamine receptor is DRD5, the treatment regimen comprises administering an effective amount of a therapeutic agent, such as a compound of formula (10) or a pharmaceutically acceptable salt thereof, and a mutation in the DRD5 gene measured in the sample indicates that the treatment regimen is effective or ineffective. In one embodiment, the dopamine receptor is DRD5, the treatment regimen comprises administering an effective amount of a therapeutic agent, such as a compound of formula (10) or a pharmaceutically acceptable salt thereof, and a missense mutation Q366R in the DRD5 gene measured in the sample indicates that the treatment regimen is effective or ineffective.
In another aspect, provided herein are methods of identifying whether a subject having a condition is likely to respond to a treatment regimen described herein. In one embodiment, the method comprises (i) obtaining a biological sample from a subject; (ii) measuring gene copy number or mutation of at least one dopamine receptor in the sample; (iii) comparing the gene copy number or the found mutation measured in the sample with a gene copy number or mutation of a predetermined standard; and (iv) determining whether the subject is likely to respond to the treatment regimen based on a comparison of the gene copy number or the mutation found in the sample to a gene copy number or mutation of a predetermined standard. In one embodiment, the subject has or is at risk of having cancer. In one embodiment, the cancer is a neurooncologic disease. In one embodiment, the cancer is a neuroendocrine tumor. In one embodiment, the cancer is selected from the group consisting of: meningiomas, ependymomas, gliomas, neuroblastomas, and diffuse endogenous pontine gliomas. In one embodiment, the subject has or is at risk of having a psychiatric disorder. For example, the psychiatric disorder is selected from psychosis, schizophrenia, bipolar disorder, and major depression. In one embodiment, the subject has or is at risk of having an infection such as a bacterial infection. In one embodiment, the infection is a gram-negative bacterial infection. In one embodiment, the infection is a gram positive bacterial infection. In one embodiment, the infection is an infection of a bacterium selected from the group consisting of: enterococcus faecium, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter bacteria. In one embodiment, the gram-positive bacterial infection is staphylococcus aureus. For example, the staphylococcal infection is a staphylococcus aureus infection (e.g., methicillin-resistant staphylococcus aureus (MRSA) infection). In one embodiment, the treatment regimen comprises administering an effective amount of a therapeutic agent, such as a compound of formula (10), a pharmaceutically acceptable salt thereof, or an analog thereof. In one embodiment, the dopamine receptor is from the D2-like family of dopamine receptors. In one embodiment, the dopamine receptor is DRD 1. In one embodiment, the dopamine receptor is
In addition, measuring expression, post-translational modification or activity levels or mutations of eIF 2-a, ATF4, CHOP, DR5, or cleaved or
In one embodiment, the subject has or is at risk of having cancer. In one embodiment, the treatment regimen comprises administering an effective amount of emiliene (e.g., ONC201) or an analog thereof. In one embodiment, the treatment regimen comprises administering an effective amount of ONC 201. In one embodiment, the treatment regimen comprises administering an effective amount of a compound of formula (10). In one embodiment, the compound of formula (10) is a compound of formula (40), for example, a compound of formula (45). In one embodiment, the compound of formula (10) is a compound of formula (50), for example, a compound of formula (55). In one embodiment, the compound of formula (10) is a compound of formula (80). In one embodiment, the compound of formula (10) is a compound of formula (90). In one embodiment, the compound of formula (10) is a compound of formula (60). In one embodiment, the structure of the analog of compound (1) is selected from the structures of formula (25), formula (26), formula (27), formula (28), formula (29), formula (30), or formula (31).
The level of the predetermined criterion may be, for example, an average or median level measured in a sample from the subject. The level of the predetermined standard may be measured under the same or substantially similar experimental conditions as the sample from the subject. The level of the predetermined criterion may be obtained from a subject responsive to treatment with an emiperidone (e.g., ONC201) or an analog thereof. In one embodiment, the predetermined criteria is obtained from a subject who is responsive to treatment with a compound, and if the level in a sample from the subject is similar to the level in the criteria, the subject may be classified as likely to be responsive to treatment. The level of the predetermined standard may be obtained from a subject who is not responsive to treatment with the compound. In one embodiment, the predetermined criteria is obtained from a subject who is not responsive to treatment with a compound, and a subject may be classified as likely to be responsive to treatment if the level in a sample from the subject is different (e.g., up-or down-regulated) from the level in the predetermined criteria. The level of the predetermined criterion may be obtained from normal healthy subjects.
Immunoassays can be used to determine the level of protein or methylation in a sample, including enzyme-linked immunosorbent assays (ELISA), enzyme-linked immunosorbent assays (ELIFA), flow cytometry, immunoblotting, immunoprecipitation, immunohistochemistry, immunocytochemistry, Luminescent Immunoassays (LIA), Fluorescent Immunoassays (FIA), and radioimmunoassays. m is6The level of amprna methylation can be obtained by methylated RNA immunoprecipitation (Me-RIP) or other quantitative biochemical assays known in the art.
Nucleic acid mutations can be determined by any of a number of procedures. For example, a biological sample is obtained from a subject. Non-limiting examples of biological samples include a bodily fluid (e.g., urine, saliva, plasma, or serum) or a tissue sample (e.g., a buccal tissue sample or buccal cells). The biological sample can then be sequenced or scanned using known methods. For example, a DNA array can be used to analyze at least a portion of the genomic sequence of a subject. In addition, whole or partial genomic sequence information may be used. Such sequences can be determined using standard sequencing methods including chain termination (Sanger dideoxynuclotide), dye terminator sequencing And SOLIDTMSequencing (Applied Biosystems, USA). The entire genome can be sequenced by restriction enzyme cleavage or (mechanical) splicing into shorter fragments. Methods such as PCR and vector-based cloning methods (e.g., E.coli) can also be used to amplify DNA sequences. In one embodiment, at least a portion of the subject's genetic material (e.g., DNA, RNA, mRNA, cDNA, other nucleotide bases, or derivatives thereof) is scanned or sequenced using, for example, a conventional DNA sequencer or chip-based technique to identify the presence or absence of mutations or copy number variants.
In one aspect, provided herein are methods of identifying and treating a subject who is likely to respond to a treatment regimen described herein and who has a condition. In one embodiment, the method comprises: (i) identifying whether a subject having a condition is likely to respond to a treatment regimen described herein; and (ii) treating a subject determined to be likely to respond to the treatment regimen with the treatment regimen. In one embodiment, the subject has or is at risk of having cancer. In one embodiment, the treatment regimen comprises administering an effective amount of emilienone (e.g., ONC201) or an analog thereof. In one embodiment, the treatment regimen comprises administering an effective amount of compound (1). In one embodiment, the treatment regimen comprises administering an effective amount of a compound of formula (10). In one embodiment, the compound of formula (10) is a compound of formula (40), for example, a compound of formula (45). In one embodiment, the compound of formula (10) is a compound of formula (50), for example, a compound of formula (55). In one embodiment, the compound of formula (10) is a compound of formula (80). In one embodiment, the compound of formula (10) is a compound of formula (90). In one embodiment, the compound of formula (10) is a compound of formula (60). In one embodiment, the structure of the analog of compound (1) is selected from the structures of formula (25), formula (26), formula (27), formula (28), formula (29), formula (30), or formula (31).
The level of the predetermined criterion may be, for example, an average or median level measured in a sample from the subject. The level of the predetermined standard may be measured under the same or substantially similar experimental conditions as the sample from the subject. The level of the predetermined criterion may be obtained from a subject responsive to treatment with an emiperidone (e.g., ONC201) or an analog thereof. In one embodiment, the predetermined criteria is obtained from a subject who is responsive to treatment with a compound, and if the level in a sample from the subject is similar to the level in the criteria, the subject may be classified as likely to be responsive to treatment. The level of the predetermined standard may be obtained from a subject who is not responsive to treatment with the compound. In one embodiment, the predetermined criteria is obtained from a subject who is responsive to treatment with a compound, and a subject may be classified as likely to be responsive to treatment if the level in a sample from the subject is different (e.g., up-or down-regulated) from the level in the predetermined criteria. The level of the predetermined criterion may be obtained from normal healthy subjects. Immunoassays can be used to determine the level of protein in a sample.
In one aspect, provided herein are methods of treating and assessing the effectiveness of a treatment in a subject having a condition. In one embodiment, the method comprises (i) treating the subject according to the treatment methods described herein and (ii) assessing the effectiveness of the treatment as described herein. In one embodiment, the subject has or is at risk of having cancer. In one embodiment, the treatment regimen comprises administering an effective amount of emiliene (e.g., ONC201) or an analog thereof. In one embodiment, the treatment regimen comprises administering an effective amount of compound (1). In one embodiment, the treatment regimen comprises administering an effective amount of a compound of formula (10). In one embodiment, the compound of formula (10) is a compound of formula (40), for example, a compound of formula (45). In one embodiment, the compound of formula (10) is a compound of formula (50), for example, a compound of formula (55). In one embodiment, the compound of formula (10) is a compound of formula (80). In one embodiment, the compound of formula (10) is a compound of formula (90). In one embodiment, the compound of formula (10) is a compound of formula (60). In one embodiment, the structure of the analog of compound (1) is selected from formula (25), formula (26), formula (27), formula (28), formula (29), formula (30), or formula (31).
Other conditions that may be suitable for use in the methods described herein include attention deficit disorders; addiction; epilepsy; viral infection; inflammation; neurodegenerative diseases, such as alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis; cardiovascular diseases, such as coronary artery disease, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, arrhythmia, inflammatory heart disease, endocarditis, inflammatory cardiac hypertrophy, myocarditis, valvular heart disease, cerebrovascular disease, peripheral artery disease, congenital heart disease, rheumatic heart disease; diabetes mellitus; and light chain amyloidosis.
V. composition
In one aspect, a pharmaceutical composition is provided, comprising formula (10):or formula (1):
Compound (1) (ONC201), which has the same chemical structure as compound NSC 350625 as shown by structural analysis (e.g., NMR, X-ray diffraction), is available from the national Cancer Institute's development Therapeutics Program library.
In one embodiment, the pharmaceutical composition comprises a di-salt (e.g., dihydrochloride salt) of ONC201 or an analog thereof (e.g., isometrione). Salts (e.g., di-or tri-salts) of the ONC201 analogs can be prepared from the ONC201 analogs, which salts can be synthesized as described herein or using standard chemical synthesis methodologies known to those of ordinary skill in the art.
In one embodiment, the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier. Non-limiting examples of suitable pharmaceutically acceptable carriers include carriers in the following documents: handbook of Pharmaceutical Excipients (handbook of Pharmaceutical Excipients), 7 th edition, edited by Raymond c.rowe et al, American Pharmaceutical Association, Washington, USA and british Pharmaceutical Press, London (London); and earlier versions. Exemplary pharmaceutically acceptable carriers, methods of making pharmaceutical compositions and various dosage forms, and modes of administration are well known in the art, for example, as described in detail in: dosage form of the drug: tablet (Pharmaceutical delivery Forms: tables), edited by larryl, augsburger and Stephen w, hoag, london: information medical health publishing company (London: InformatHealthcare), 2008; and l.v. allen, jr. et al, "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Ansel's Pharmaceutical Delivery Forms and Drug Delivery Systems), 8 th edition, philadelphia, pa: ripidote Williams and Wilkins publishing company (Philadelphia, Pa.: Lippincott, Williams & Wilkins), 2004; gennaro, redmington: in The pharmaceutical sciences and practices (Remington: The Science and practice of Pharmacy), Lepidote Williams and Wilkins publishing company, 21 st edition, 2005, in particular Chapter 89; hardman et al, Pharmacological Basis for Therapeutics in Goodman & Gilman's the Pharmacological Basis of Therapeutics, McGraw-Hill Professional publishing company (McGraw-Hill Professional), 10 th edition, 2001.
In one embodiment, the pharmaceutical composition is formulated for ocular administration. In one embodiment, the pharmaceutical composition is formulated for topical administration. In one embodiment, the pharmaceutical composition is formulated as drops, ointment or liquid. In one embodiment, the pharmaceutical composition comprises a conventional pharmaceutical carrier, such as an aqueous, powdery or oily base, a thickening agent.
In one embodiment, the pharmaceutical composition is a formulation for intravenous administration. In one embodiment, the intravenous formulation comprises a compound of formula (10) or a pharmaceutically acceptable salt thereof dissolved in a solvent. In one embodiment, the solvent comprises water. In one embodiment, the intravenous formulation comprises a compound or salt thereof at a concentration of about 0.05, about 0.25, about 0.5, about 2.5, about 5, about 25, or about 50 mg/mL. In one embodiment, the intravenous formulation comprises a compound or salt thereof in a concentration of about 0.05, 0.5, or 5mg/mL to about 1, 10, or 100 mg/mL. In one embodiment, the intravenous formulation comprises from about 0.005%, 0.05%, or 0.5% to about 0.1%, 1%, or 10% of the compound or salt thereof. In one embodiment, the intravenous formulation comprises about 0.05%, 0.5%, or 5% of the compound or salt thereof. In one embodiment, the intravenous formulation comprises a higher or lower concentration of the compound or salt thereof.
In one embodiment, the intravenous formulation has a pH of about 3. In one embodiment, the formulation is adjusted to a pH of 3 with a phosphate buffer. In one embodiment, the intravenous formulation comprises dextrose or sodium chloride. In one embodiment, the intravenous formulation comprises a compound or salt thereof at a concentration of about 5mg/mL and a pH of 3 and forms a stable solution. In one embodiment, the intravenous formulation comprises a compound or salt thereof at a concentration of about 5mg/mL and a pH < 5 and forms a stable solution. In one embodiment, the intravenous formulation comprises a compound or salt thereof and one or more antioxidants. In one embodiment, the intravenous formulation comprises a mixture of mono-and di-hydrochloride salts of the compound. In one embodiment, the intravenous formulation comprises a concentration of the compound or salt thereof in a 1% solution of about 10 mg/mL. For example, the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.
In one embodiment, a suitable pharmaceutically acceptable carrier comprises an aqueous carrier. In one embodiment, the aqueous carrier comprises sterile water. In one embodiment, the formulation comprises dextrose, sodium chloride, or both. In one embodiment, the pharmaceutically acceptable carrier comprises an oil.
In one embodiment, the intravenous formulation comprises ONC201 or its analog or its dihydrochloride dissolved in water at 25 mg/mL. In one embodiment, the formulation is adjusted to a pH of 3 with a phosphate buffer. In one embodiment, the formulation comprises dextrose, sodium chloride, or both. In one embodiment, the formulation comprises a higher or lower concentration of the dihydrochloride salt of ONC201 or its analogs. In one embodiment, the formulation comprises ONC201 or its analog or its dihydrochloride salt at a concentration of about 5 mg/mL. In one embodiment, about 5mg/mL of the formulation forms a stable solution and has a pH of 3. In one embodiment, about 5mg/mL of the formulation has a pH < 5 and forms a stable solution. In one embodiment, the intravenous formulation comprises ONC201 or an analog thereof or a dihydrochloride thereof and one or more antioxidants. In one embodiment, the intravenous formulation comprises a mixture of mono-and di-hydrochlorides of ONC201 or an analog thereof. In one embodiment, the intravenous formulation comprises ONC201 or its analog or its dihydrochloride salt in a 1% solution at a concentration of about 10 mg/mL. For example, the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.
In one embodiment, the intravenous formulation comprises from about 0.5% to about 10% (or from about 5mg/mL to about 100mg/mL) ONC201 or an analog thereof or a disalt thereof. In one embodiment, the formulation comprises about 5% (or about 50mg/mL) ONC201 or its analog or a disalt thereof. In one embodiment, the intravenous infusion rate may be slowed to reduce side effects of ONC201 or its analogs or disalts thereof.
In one embodiment, the pharmaceutical composition comprises about 0.1-99% ONC201 salt or analog thereof; and a pharmaceutically acceptable carrier, for example, an oil or sterile water or other aqueous carrier. In one embodiment, for an oral dosage form, the composition includes a range of about 5% to about 50% of a mono-or di-salt of ONC201 or its analog.
In one embodiment, the pharmaceutical composition comprises an antioxidant. Suitable antioxidants include: ascorbic acid derivatives, such as ascorbic acid, erythorbic acid, sodium ascorbate; thiol derivatives, such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythritol (dithioerythritol), dithiothreitol, glutathione, tocopherol, Butylhydroxyanisole (BHA), Butylhydroxytoluene (BHT); sulfites such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, and sodium thiosulfate; nordihydroguaiaretic acid. It should be noted that antioxidants for aqueous formulations typically comprise: sodium sulfite, sodium metabisulfite, sodium formaldehyde sulfoxylate or ascorbic acid and combinations thereof, while antioxidants for oil-based solutions, organic solvents comprise BHT, BHA or propyl gallate and combinations thereof. In still other embodiments, the antioxidant may be one or more of the following: flavonoids, isoflavones, thioglycerol, L-cysteine, thioglycolic acid, alpha-tocopherol, ascorbic acid 6-palmitate, dihydrolipoic acid, BHT, BHA, vitamin E, propyl gallate, beta-carotene and ascorbic acid. Antioxidants can generally be used at about 0.1 wt% to 1.0 wt%, more typically about 0.2 wt%.
In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent. For example, the additional therapeutic agent is selected from the group consisting of: hormone analogs and anti-hormones, aromatase inhibitors, LHRH agonists and antagonists, growth factor inhibitors, growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors; an antimetabolite; an anti-tumor antibiotic; a platinum derivative; an alkylating agent; an anti-mitotic agent; a tubulin inhibitor; PARP inhibitors, topoisomerase inhibitors, serine/threonine kinase inhibitors, tyrosine kinase inhibitors, protein interaction inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogues, BTK inhibitors, CRM1 inhibitors (e.g., KPT185), P53 modulators (e.g., imidazoline analogues (Nutlins)), anti-angiogenic drugs (e.g., axitinib, aflibercept, sorafenib and regorafenib), amifostin (amifostin), alogenlide (anagrelid), croudlarjasite (clodronat), filgrastin (filgrastin), interferons, interferon alpha, folinic acid, rituximab (rituximab), procarbazine (carprofazine), levamisole (sodium), mestran (sodium), sodium (sodium), disodium ferulate (sodium), and phenanthrenene (sodium), pamirpex (sodium), pamidronate (sodium), and pamirpint (sodium), 2-chlorodeoxyadenosine (2-chlorodesoxyyadenosine), 2-fluorodeoxy-cytidine (2-fluorodeoxyadenosine-cytidine), 2-methoxyestradiol (2-methoxyestRadiol), 2C4, 3-alidomide (2C4,3-alethine), 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B (16-aza-epothilone B), A105972, A204197, abiraterone (abiraterone), aldesleukin (aldesleukin), aliquoid (alitretinoin), alovermectin-7 (allovitexin-7), hexamethomelamine (altretamine), alloxydim (alvocidib), amonafide (amonafide), anthrapyrazole (amythraparadoxazone), aprazapine (AP-80), apocynine (apocyn-aldioxane-7), apocyn-7 (aamyl AG), apocynine (apocyn-80), apocynine (apocyn- α -r-e), apocyn- α -r (apocyn-r-7), apocyn-p-r-p-r, Arglabin (arglabin), azidime (arzoxifene), atamestan (atamestane), atrasentan (atrasentan), orlistatin-PE (auristatin PE), ABT-199 (Venetobactam), ABT-263 (Navitolax), AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab)), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (Semitanib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZE-44, ARQ-736, AS-302680, AS-3026 (arzoxib), azalasiodiplob (azalasiodiplob), azaspiramycin (azaspiramycin), azaspiramycin (20144), azaspiramycin (E-20144), azaspiramycin (azaspiramycin B), azaspiramycin (E-20146 (azaspiramycin B), azaspiramycin (E-2014-E), and E-E (E-E) Arzonafide (azonafide), BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, bevacizumab (bevacizumab), BEZ-235, Biercoda bicitric acid (bicicolar dicitrate), BCX-1777, BKM-120, bleomycin (bleocin), BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (afatinib), Touttatoka (tomtovack), BIBF 1120 (varvatobb), BI836845, BI 2536, BI 6727, BI 684835, BI 847325, BI 853520, BUB-022, bleomycin (bleomycin), bleomycin A-1 b, blebbb (blebbb), blebbb 1 b-1, blebbb (blebbb), blebbb-1, blebbb-b (blebbb) blebbb, blebbb-b, blebbb (blebbb) blebbb-b, blebbb-b, blebbb-, Bortezomib (bortezomib), broustrine (brosplalcin), busulfan (busulphan), BYL-719, CA-4 prodrug, CA-4, cap cells, calcitriol (calceinol), canertinib (canertinib), canfosfamide (canfosfamide), capecitabine (capecitabine), carboplatin carboxyphthalate (carbopxhalalatoxin), CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1cefixime (CBT-1cefixime), cephalotaxine (ceflatatin), ceftriaxone (cefatrixone), celecoxib (celecoxib), simoleukin (momoleukin), cimadrein (cemadotin), CH/87655/4987655, chlorenoxatrine (4987655), cloxacillin (CDC-3527), colchicine (CDC-3527), cloxacitabine (CDC-3527), CIE (CDC-A), CIRCR-3527, CII (CIRCA), CIRCR-1, CII), CIRCR-1, CIBIN, CII (CII), CIRCR-1, CII), CII (CIRCI), CII (CII), CIRCI (CIRCI), CIRCI (CIRCI), CIRCI, COT inhibitor, CHS-828, CH-5132799, CLL-tera (CLL-Thera), CMT-3cryptophycin 52(CMT-3cryptophycin 52), CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, phycoerythrin doxorubicin (cyanomorphinodubericin), cytarabine (cytarabine), D24851, decitabine (decitabine), deoxobicin (deoxomicin), deoxomicin (deoxomicin), deoxosynomycin (deoxomycetomomycin), depsipeptide (depsipeptide), deoxoepothilone B (desoxyepothilone B), dexamethasone (dexamethasone), dexrazoxane (dexrazoxane), diethylstilbestrol (diethelitate), difluorixadiol (difluorexin), doxolone (doxolone), doxorabicolone (doxoramide (DML-thetase), doxoramide (D-7410), doxorazole (DMT-10), doxoramide (DMT-7410), doxoramide (D), doxoramide (D) (DMT-7423), doxoramide (doxoramide), doxoramide (D), doxoramide (doxoramide), doxoramide (D), doxoramide (D, Enlonicet (eflornithine), EGFR inhibitor, EKB-569, EKB-509, enzastarin (enzastaurin), enzalutamide (enzalutamide), elsamitrucin (elsamitutricin), epothilone B (epothilone B), epratuzumab (epratuzumab), ER-86526, erlotinib (erlotinib), ET-18-0CH3, ethinyl cytidine (ethylcytidine), ethinyl estradiol (ethylylestiadiol), irinotecan (exatecan), irinotecan (irinotecan) mesyl acid, exemestane (exemestane), sulindine (exisulindide), vephenamide (fenretinide), phenanthroidamycin (filgitotuzumab), floxuridine (floxuridine), LFOX, FO 4, FOLII (FOLIX), FOMSI (FORGE), FOMSE (FOMSE), FOMSE (FOG (FOMSE), FOMSE (E), FOMSE (FOMSE), FOMSE (E), FOMSE (E), FOMSE), EPE (E), EPE, GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp 100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron (granisetron), herceptin (herceptin), hexamethyelmamine (hexamethyelmamine), histamine, homoharringtonine (homoharringtonine), hyaluronic acid, hydroxyurea, hydroxyprogesterone (hydroxyprogesterone citrate), bamestramustine phosphonate (ibandronate), ibrutinate (imipenemate), IGF (IMritate), ibrinomycin C-5109, estramurtib (I-1, morubicine A-392016 (I), morganine (I-A-3, IMITC-392016 (rituximab), and optionally, IMK-3 (rituximab (I), and optionally, I-D-5 (I), and optionally, I, and so as well as a, Immunology, Induslam (indesulam), interferon alpha-2 a, interferon alpha-2B, peginterferon alpha-2B, interleukin-2, INK-1117, INK-128, INSM-18, jonafanib, Yiprimumab (ipilimumab), isoplatinum (iproplatin), ifosfen (irofulven), isophoroneB (isohalophalichodrin-B), isoflavone (isoflazone), isotretinoin (isotretinoin), ixabepilone (ixabepilone), JRX-2, JSF-154, J-107088, conjugated estrogens, Carragolide F (kahalid F), ketoconazole (ketoconazole), KW-2170, KW-0, lobaplatin (lobaplatin), lexolite (leflacci), leflunomide (unlamine), leuprolide (propiverine), propiolactone (1550), leuprolide (rolidine), neviramide (oxlide (e), nevirapine (D), leuprolide (1550), leuprolide (e-B), and pharmaceutically acceptable salts thereof, Motexaphyrin (lutetium texaphyrin), lometrexol (lomerexol), losoxantrone (losoxantrone), LU 223651, lurtotecan (lurtotecan), LY-S6AKT1, LY-2780301, macsfamide (mafosfamide), maristat (marimastat), mechlorethamine (mechlorethamine), MEK inhibitor, MEK-162, methyltestosterone (methylesteroson), methylprednisolone (methylprednisone), MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin (midostaurin), minodronic acid (minodronic acid), mitomycin, mivobulin (mivobulin), Mivobulin-6, Mizoxan-0646 (luteolin), MK-25, neratinib (mlnetorubine), neratinib (MK-6, neratinib (mlnetovanib), neratidine (MLN-275), neritinib (mlovanib), neritinib (MLN-2209), neratinib (MK-275), neritinib (neritinib), neritinib (MLN-25), neratinib), neritinib (MLN-275), neritinib (Mivone, neritinib), and (Mitsumadicine, Mitsunobarb, Mitsumadicine, Mitsumadorigine (Mi, Nimesulide (nimesulide), nitroglycerin, loratrexed (nolatrexed), norlin (norelin), N-acetylcysteine, 06-benzylguanine, obimersen (oblimesen), omeprazole (omeprazole), conephage (oncophage), VEXGM-CSF, ormiplatin (ormoplatin), otaxel (ortataxel), OX44 antibody, OSI-027, OSI-906 (linsitinib)), 4-1BB antibody, oxatansole (oxantazole), estrogen, panitumumab (panitumumumab), patopilone (patupilone), pefilgrastim (pegfilstim), PCK-3145, pefilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-taxol, paclitaxel, PHP-005, PEPTE-P-33, PEPT-36, PEPT-3632, PEPT-PF-3632, PEPT-3632, pP-3618, pP-3688, pP-3632, pP-3618, pP-3, pP, pelitinib (pelitinib), pemetrexed (pemetrexed), pendrix (pendrix), perifosine (perifosine), perillyl alcohol (perillidolol), pertuzumab (pertuzumab), PI3K inhibitor, PI3K/mTOR inhibitor, PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin (picoplatin), pivaloyloxymethylbutyrate (pivaloyloxymethylbutyrate), pixantroxytron (pixantronolone), diphenolo (phenoxodolol o), PKI166, pleviruexed (plevixexed), plicamycin (plicamycin), polypentactin (polypentactin), polymannuin (rapetrexed), prednisolone (ramycin), prednisolone (R) 7766, prednisolone (prednisone), prednisone (triamcinolone (R), prednisolone (triamcinolone 97265), prednisone (prednisone), prednisolone (triamcinolone), prednisone 977, prednisone (prednisone), prednisolone (triamcinolone), prednisolone (triamcinolone), prednisolone acetonide), prednisolone (triamcinolone acetonide), prednisolone (triamcinolone acetonide), prednisolone aceton, RDEA-436, Rebeccamycinalogs, Receptor Tyrosine Kinase (RTK) inhibitors, regorafenib (rinfabate), thalidomide analogs (revimid), RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, lisofenin (rhizoxin), rhu-MAb, Rinfibrine (rinfabate), risedronate (risedronate), rituximab (rituximab), Rotuzumab (robitumumab), rofecoxib (rofecoxib), RO-31-7453, RO-5126766, RO-5068760, RPR109881A, norbizozide (rubidazole), rubitecan (rubitecan), R-flurbiprofen (R-flurbiprofen), RX-0201, S-9788, sarstinstin (SAubstatin), SAubsalazine (SARG), SARGSARG-015, SARGSARGSANSIS-SANSIS (SARGSARG), SUS-9788, SARGSARGSARGSARG (SARGSARGSARG-SARG), SARGSARG-SARG, SARG-SARG (SARG-SARG), SARG-SARG), SARG-, Seocalcitol (seocalcitol), SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib (sorafenib), spiroplatinum (spiroplatin), squalamine (squalamine), anilino hydroxamic acid (suberanilic acid), sotripan (sutent), T900607, T138067, TAK-733, TAS-103, tacrolidine (tacedinalinalinine), talaporfin (talaporfin), terkshirta (Tarceva), tariquide (taritinquiqur), tassolam (tasisullam), taxotere (tattaxotere), taxol (tazaprinoxin), tazarotene (tazarotenine), tefluthrin (tetrazotoxin), tetrodotoxin (tetrodotoxin), tetramethrin (texolone), texolone (texolone), texolone (texolone), texolone (texolone), texolone (texo, Thymalfasin (thymolfasin), thymosin (thymofectin), thiazolecarboxidine (tiazofurin), tipifarnib (tipifarnib), ranitidine (tomodex), tirapazamine (tirapazamine), tolladesine (tocladesine), tolremofen (toremifin), trabectedin (trabectedin), transMID-107, transretinoic acid (transretinic acid), tretinoin (tretinoin), trastuzumab (traszuzumab), tremelimumab (tremelimumab), triacetyluridine (triacetyluridine), triazepine (triapine), triciribine (triciribine), trimetrexate (trimetrexate), TLK-286, TXk-286, tebuclizumab (verkerb/tyurrypsin), uracil (valosin), penthridine (pivirin), vincialidine (Wylovir XL), vincilurin (Wolinine (Wolinox), vincilurin-25 (Wolinox), vincristine (Wolinine), vincristine (Wolinine (Wvinifer XL), vincristine (Wviniferine), vincil-554, vincristine (Wviniferine), viniferine), vincil-25), viniferine (Wviniferine), viniferine (Wviniferine), viniferine (Wvin, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, sodium zoledronate (zoledronate), zoquinacrid (zosuquidar), and combinations thereof.
In one embodiment, the additional therapeutic agent comprises a hormone analog, an anti-hormone, or both selected from the group consisting of: tamoxifen (tamoxifen), toremifene (toremifene), raloxifene (raloxifene), fulvestrant (fulvestrant), megestrol acetate (megestrol acetate), flutamide (flutamide), nilutamide (nilutamide), bicalutamide (bicalutamide), aminoglutethimide (aminoglutethimide), cyproterone (cyproterone acetate), finasteride (finasteride), buserelin acetate (buserelin acetate), fludrocortisone (flucyclortisone), fluorometholone (fluoroxymesterone), medroxyprogesterone (medroxy-progasterone), octreotide (octreotide), and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more LHRH agonists selected from the group consisting of: goserelin acetate (goserelin acetate), luprolide acetate (luprolide acetate), triptorelin pamoate (triptorelin pamoate), and combinations thereof, and wherein the LHRH antagonist is selected from Degarelix (Degarelix), Cetrorelix (Cetrorelix), Abarelix (Abarelix), Ozarelix (Ozarelix), Degarelix, and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more growth factor inhibitors selected from the group consisting of: platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF), Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER), and Hepatocyte Growth Factor (HGF). In one embodiment, the additional therapeutic agent comprises one or more human epidermal growth factor inhibitors selected from HER2, HER3, and HER 4. In one embodiment, the additional therapeutic agent comprises one or more tyrosine kinase inhibitors selected from the group consisting of: cetuximab (cetuximab), gefitinib, imatinib (imatinib), lapatinib (lapatinib) and trastuzumab, and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more aromatase inhibitors selected from: anastrozole (anastrozole), letrozole (letrozole), liarozole (liarozole), vorozole (vorozole), exemestane, atamestan and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more antimetabolites which are antifolates selected from the group consisting of methotrexate, raltitrexed (raltitrexed), and pyrimidine analogs. In one embodiment, the additional therapeutic agent comprises one or more antimetabolites which are pyrimidine analogs selected from the group consisting of 5-fluorouracil (5-fluoroouracil), capecitabine, and gemcitabine (gemcitabine). In one embodiment, the additional therapeutic agent comprises one or more antimetabolites which are purine and/or adenosine analogues selected from the group consisting of: mercaptopurine (mercaptoprine), thioguanine (thioguanine), cladribine (cladribine) and pentostatin (pentostatin), cytarabine, fludarabine (fludarabine), and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more anti-tumor antibiotics selected from the group consisting of: anthracyclines (anthracyclines), doxorubicin (doxorubicin), daunorubicin (daunorubicin), epirubicin (epirubicin) and idarubicin (idarubicin), mitomycin-C, bleomycin, dactinomycin (dactinomycin), plicamycin (plicamycin), streptozocin (streptozocin), and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more platinum derivatives selected from the group consisting of: cisplatin (cissplatin), oxaliplatin (oxaliplatin), carboplatin (carboplatin) and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more alkylating agents selected from the group consisting of: estramustine (estramustine), mechlorethamine hydrochloride (meclorethamine), melphalan (melphalan), chlorambucil (chlorambucil), busulfan, dacarbazine (dacarbazin), cyclophosphamide, ifosfamide, temozolomide, nitrosoureas (nitrosoureas), and combinations thereof. In one embodiment, the additional therapeutic agent comprises a nitrosourea selected from the group consisting of: carmustine (carmustin), lomustine (lomustin), thiotepa (thiotepa) and combinations thereof. In one embodiment, the additional therapeutic agent comprises an antimitotic agent selected from Vinca alkaloids (Vinca alkaloids) and taxanes (taxanes). In one embodiment, the additional therapeutic agent comprises one or more taxanes selected from the group consisting of: paclitaxel, docetaxel, and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more vinca alkaloids selected from the group consisting of: vinblastine (vinblastine), vindesine (vindesin), vinorelbine (vinorelbin), vincristine, and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more topoisomerase inhibitors that are epipodophyllotoxins (epipodophyllotoxins). In one embodiment, the additional therapeutic agent comprises one or more epipodophyllotoxins selected from the group consisting of: etoposide and albuterol, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more serine/threonine kinase inhibitors selected from the group consisting of: PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK inhibitors, aurora kinase inhibitors, and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more tyrosine kinase inhibitors that are PTK2/FAK inhibitors. In one embodiment, the additional therapeutic agent comprises one or more protein-protein interaction inhibitors selected from the group consisting of: IAP, Mcl-1, MDM2/MDMX, and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more rapamycin analogs selected from the group consisting of: everolimus (everolimus), temsirolimus (temsirolimus), ridaforolimus (ridaforolimus), sirolimus (sirolimus), and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more therapeutic agents selected from the group consisting of: amifostine, alogralide, claudltarget, filgrastim, interferon alpha, folinic acid, rituximab, procarbazine, levamisole, mesna, mitotane, disodium pamidronate and porfield sodium and combinations thereof. In one embodiment, the additional therapeutic agent comprises one or more therapeutic agents selected from the group consisting of: 2-chlorodeoxyadenosine, 2-fluorodeoxy-cytidine, 2-methoxyestradiol, 2C4, 3-alicine, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alretinoin, alovermectin-7, altretamine, alloxidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apazidone, apomorphine, aronostoc, arglabin, acibenzolar, altretamine, atrasentan, orlistatin-PE, ABT-199 (venetok), ABT-263 (nevetetoavs), LB, AZ10992, ABX-EGF, AMG-479 (gantuzumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (sematinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ680, AS-703026 (primimacetobu), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-188235, bicitric acid bicifc acid, BCX-1777, BKM-120, bleomycin, BLP-25, BMS-184476, BMS-247550, BMS-52797, BMS-527991, BMS-27 754807, BMS-663513, BMS-35 754807, BMS-663513, BMS-7550, BMS-52797, BMS-277991, BMS-35 754807, BMS-663513, BMS-8025, BMS-8050, and bmps-8055, BNP-7787, BIBW 2992 (afatinib, Turkey), BIBF 1120 (nintedanib), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI853520, BUB-022, bleomycin acid, bleomycin A, bleomycin B, brimonib, bryostatin-1, bortezomib, brezostorine, busulfan, BYL-719, CA-4 prodrug, CA-4, capping cells, calcitriol, canertinib, canfosfamide, capecitabine, carboplatin carboxyphthalate, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1-cloxime, homoharringtonine, ceftriaxone, celecoxib, simons, cimetidine, CH 8749655/RO-87655, clenbuterol, cecin, CDII-49A-49655, CDC-394, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-tylan, CMT-3 candidin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247, rhodotoxin doxorubicin, arabinoside, D24851, decitabine, desoxybixin, desoxybiacin, desoxysynbiotine, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflutecan, doxus, DMDC, Dolaborin 10, doladazole, DS-7423, E7010, E-6201, Adriacetamide, Epigosamide, Esperoxyloxib, Ennesium, EGFR inhibitors, EKB-569, EKB-509, Enzadrine, bleomycin, Egylorubicin, Egyptine B, Epstein B, Epazulizumab, ER-86526, erlotinib, ET-18-0CH3, ethynylcytidine, ethinylestradiol, irinotecan mesylate, exemestane, veboxamide, feijimab, floxuridine, folic acid, FOLFOX4, FOLFIRI, formestane, fotemustine, garrubicin, maltogallium, gefitinib, gemtuzumab ozolomide, gemmace, glufosfamide, GCS-100, GDC-0623, GDC-0941 (Picklesp), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp 100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1122 (GSK-1122), GSK-Trimertinib (GSK-21136), GSK-644658, GSK-645958, GSK-648458, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptin, hexamethamidine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab tiuxetan, edatrexate, estrenol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cetuximab), immunology, addison, interferon alpha-2 a, interferon alpha-2B, pegylated interferon alpha-2B, interleukin-2, INK-1117, INK-128, INSM-18, johnenib, primima, iproplatin, ilonffin, isohalomethancholic acid B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, Califorf, Hardrada, conjugated estrogens, and, Ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lengstin, leuprorelin, riobol, lesimedean, LGD-1550, linezolid, motroxafine lutetium, lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, LY-2780301, macsfamide, marimastat, mechlorethamine, MEK inhibitor, MEK-162, methyltestosterone, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minophen, mitomycin, mifubulin, MK-2206, MK-0646 (Madazuzhuizumab), MLN518, motesafen gadolinium, MS-209, MS-MX, 275 6, neridronic acid, lenalitinib, valcanicillin, canertinib, neritinib, nitrofuramicin, nitrofuramil, neritinib, Mitsunamine, Mitsu, Loratadine, norlin, N-acetylcysteine, 06-benzylguanine, opilison, omeprazole, confei, tumor VEXGM-CSF, ormiplatin, otaxel, OX44 antibody, OSI-027, OSI-906 (Rivastigrinib), 4-1BB antibody, oxisartan azole, estrogen, panitumumab, panopiptan, pefilgrastim, PCK-3145, pefilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, peziricires, pervirginine, perbizicin, perituzumab, tuzumab, PI K inhibitor, PI 3/mTOR 3, PG K/mTOR inhibitor, PG-59L-906 inhibitor, 4-1 (Rivastigrinitinib), 4-1BB antibody, PEPTX-D-, PG2, PLX-4032/RO-5185426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxydiphenol O, PKI166, prallethricin, plicamycin, polyglutamic acid, methylmitomycin, prednisone, prednisolone, quinindide, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY869766, RDEA-436, butterfly-mycin analogs, Receptor Tyrosine Kinase (RTK) inhibitors, thalidomide analogs, RG-7167, RG-7304, RG-7421, RG-7321, RG 40, lisoprotein, 74 rhu-MAb, linfrifferian, rituximab, rofecoxib, RO-7453, RO-7431-7453, and RO-7453, RO-5126766, RO-5068760, RPR 109881A, nordipicolinate, rubitecan, R-flurbiprofen, RX-0201, S-9788, sarubicin, SAHA, sargrastim, satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, anilinoisohydroxamic acid, sotriptan, T900607, T138067, TAK-733, TAS-103, tacroline, talaporfin, tarceva, tacrine, tasolamide, taxotere, tazarotendine, tixodine, temozolomide, testosterone, tetramiflamol, tezomib, teflunixifen, texate, texapride, tetrodotoxin, tizacitabine, thalidomide, tyloxapol, tetrahydropyran doxorubicin, thymalfasin, thymosin, thiazolecarboxamide nucleoside, tipifarnib, raltitrexed, tirapazamine, tolazadine, tolrimofen, trabectedin, trans MID-107, trans-retinoic acid, trastuzumab, tremelimumab, triacetyluridine, triazepine, triciribine, tritrexate, TLK-TXD 258, tykebo (tykerb/tyverb), uracil, valrubicin, varenidine, vincristine, vinflunine, a vitamin such as ritin, WX-UK1, WX-554, panitumumab, hiloda, XELOX, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-90, ZD-5990, ZD-415990, ZD-5990, and trematodine, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, sodium zoledronate, azaquinad and combinations thereof.
In one embodiment, the additional therapeutic agent comprises a steroid comprising dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cocazole (Cortivazol). In one embodiment, the other therapeutic agent includes an antiemetic agent including, but not limited to, 5-HT3 receptor agonists (e.g., dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine); dopamine agonists (e.g., domperidone (domperidone), olanzapine (olanzapine), droperidol (droperidol), haloperidol (haloperidol), chlorpromazine (chlorpromazine), prochlorperazine (prochlorperazine), alizapride (alizapride), prochlorperazine, and metoclopramide)); NK1 receptor antagonists (e.g., aprepitant and casotetherein); antihistamines (such as cyclizine, diphenhydramine, dimenhydramine, doxylamine, meclizine, promethazine, hydroxyzine); cannabinoids (e.g., cannabis (cannabibis), dronabinol (dronabinol), cannabirone (nabilone) and saritex (sativex)); benzodiazepines (e.g., midazolam (midazolam) and lorazepam); anticholinergic classes (e.g., scopolamine (hyoscine)); trimethoxybenzamide (trimethobenzamide); ginger; yutuning (emetrol); propofol (propofol); mint; muscimol (muscimol) and caraway (ajwain) of india.
In one embodiment, the additional therapeutic agent comprises an anti-cancer agent comprising a mitotic inhibitor. In one embodiment, the mitotic inhibitor comprises a taxane. In one embodiment, the mitotic inhibitor comprises a taxane selected from paclitaxel and docetaxel.
In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof; and at least one anti-cancer agent comprising one or more of: acivicin (acivicin), aclarubicin (aclarubicin), acidazole (acodazole), acloninine (acronine), adolesin (adozelesin), aldesleukin, alivecarboxylic acid, allopurinol (allopurinol), altretamine (ambomamycin), ambomycin (ambomamycin), amethrone (tanatrone), amifostine, aminoacridine, anastrozole, amphenycin (antramycin), diarsenic trioxide (arsenical trioxide), asparaginase (asparagenase), triptyline (aspergilin), azacitidine (azacitidine), azatepa (azetepa), azomycin (azomycin), batimastat (batin), batimastat (batidine), batimastastatin (batit), bentepa (benzozelesin), bevadine, bivalinamide (bivalinate), bisquinase (dipine), pyrimethanil (pyrimethanil), pyrimethanil (pyrimethamine), pyrimethanil (pyrimethanil), pyrimethamine (brevudine), pyrimethanil (brevicine), pyrimethanil (ibacil), pyrimethamine (ibacil (beraprotinine), pyrimethamine (ibacil (berberizine), pyrimethamine (berberidazine), pyrimethamine (e), pyrimethanil (berbenproperine (benproperine), pyrimethamine), pyrimetha, Carbitemer (carbetimer), carboplatin, carmustine, carubicin (carubicin), carmalexin (carzelesin), cedarf iotanger (cedefingol), celecoxib (celecoxib), chlorambucil, sirolimus (cirolemycin), cisplatin, cladribine, clemastine (crisnatomesylate), cyclophosphamide, arabinoside, dacarbazine, actinomycin, daunomycin, decitabine, dexmaplatin (dexrmatoplatin), dizuanine (zadeguanine), dizuanine (diazanazinone mesylate), sillimone (diaziquone), docetaxel, doxorubicin (doxorubin), droloxifene (droloxifene), drotalarone (dronololone), daloxanthin (dalziridin), epirubicin (epiloxapine), epiloxifen (epiloxifenproxyproline), epiloxifenplatin (estramurenone (epiloxacin), epiloxacin (loxacin), norgestimatine (loxacin), doxicane (loxacin), loxacin (loxacin), loxacin (lox, Etanidazole (etanidazole), etoposide (etoprine), fadrozole (fadrozole), fazarabine (fazabine), tretinomide (fenretinide), floxuridine (floxuridine), fludarabine, fluorouracil, flurocitabine (flurocitabine), feiquidone (fosquidone), fostrexed (fosstricin), fulvestrant, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imofofenacin (ilmofosine), interleukin II (IL-2, including recombinant interleukin II or rIL2), interleukin alpha-2 a, interleukin alpha-2 b, interleukin alpha-n 1, interleukin alpha-n 3, interleukin beta-Ia, interleukin gamma-Ib, iproplatin, irinotecan, remoxatrinide (letrexadone), letrozole, leuprolide (leuprolide), leuprolide (loxacine), leuprolide (loxacin), trogliptin (fludarunavoide), fludarunavoidine, fludarabine (fossilidone, fludarunavoidine), fludarabine, fludarunavoidine, fludarosine, IL-2, and leuprolide, Masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melphalan, methonuril, mercaptopurine, methotrexate, chlorpheniramine, metotepa, mitodomide, mitomonocarb, mitocarcin, mitopuromycin, mitosporine, mycophenolic acid, nerabine, nelumbilicin hydrochloride, neomycin, neopheniramide, pentaerythrasmine hydrochloride, neopheniramide, pentamycin hydrochloride, pentazocine hydrochloride, melloperamide, melphalan, doxin, melphalan (oxypendymycin, melphalan, mel, Plicamycin (plicamycin), pramipentane (plomestane), porfil sodium, mitomycin, prednimustine (prednimustine), procarbazine (procarbazine), puromycin (puromycin), pyrazolofuranin (pyrazofurin), liberadenosine (ribopine), rogurimide (rogletimine), safrogol (safrogoglol), semustine (semustine), octreozine (simtrazine), aspartyl (spartate), sparamycin (spiomycin), germanospiroamine (spirogimeramine), spiromustine (spiromustine), spiroplatin, streptomycin (streptonigrin), streptozotocin (streptozocin), benzosulfonurea (sulufuryr), talmycin (talisomycin), cetrimine (mycophenoleotaxine), tipetretinotene (mycophenolide), pterosin (oxypurin), thioredoxin (pyridoxine), thioredoxin (pyridoxine), thioredoxin (pyridone), thioredoxin (pyridoxine), thioredoxin (thioredoxin), thioredoxin (thioredoxin), topotecan, toremifene, tritulone, triciribine, trimetrexate, triptorelin (triptorelin), tobrozole (tubulozole), uramustine (uracilmustard), uredepa (uredepa), vapreotide (vapreotide), verteporfin (verteporfin), vinblastine, vincristine sulfate (vinristine sulfate), vindesine, vinepidine (vinopidine), vinglycinate (vinglyinate), vincristine (vinleutosine), vinorelbine (vinrosidine), vinrosidine (vinzolidine), vorozole, zeniplatin (zeiplatin), zinostat (zinostat), zoledronate (zodronate), zorubicin (zorubicin), and combinations thereof.
In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof; and at least one anti-cancer agent comprising one or more of: loratatinib (LORBRENA), pembrolizumab (pembrolizumab) (KEYTRUDA), tazoledrine (talazoparib) (TALZENNA), eimeistocida-kxwhh injection (EMIClizumab-kxwhh injection) (HEMLIMLIBRA), cimipipril-rwlc (CEmiplimab-rwlc) (LIBTAYO), dacomitinib tablet (dacomitinib tablets) (VIZIMPRO), duvetib (Duvelisib) (COPIKTRA), pamocib-tdfk (moxetumomastidox-tdfk) (LUMOXIzox-tdfk) (LUMOXIMATI), Nwaruzumab (OPNIVOQVO) (DIVO), MoGAMULISUMPKc (mogali-Kpkum), Mugaoliguri (Macadi-KpIiboE) (PoRBOMATI), Pimpinoxyme (Pimpinoxyme), Mukutpuribepotivi (AOI), Mugauci-mex (Pimpinox-mex (Ivortici), Mukumi (Pimpi-mex (Ii), Pimpi (Pimpi-mex), Murra (Pimpi-mex), Murra (Pimpi-mex), Murra-mex (Pimpi-mex), Murra (Pimpi-Iben-mex (Pimpi-me, Encochlonib and bimetinib (BRAFTOVI and MEKTOVI), bevacizumab (avastin), Venetock (VENCLEXTA), methoxypolyethylene glycol-epoetin beta (methoxy polyethylene glycol-epoetin beta) (miloperate), felbina (furphila) (pefilgratin-jmdb), avapro (avapore) (doptelate), retacort (Retacrit) (epoetin-epbx), selefuramel (tigeleceucuel) (mrkyiah), danafinil (tanflar), tritertinib (meripatientin), tablet sodium (ninilapamide), tablet sodium (nigella), nilla (vitamin sodium), tablet sodium (vitamin citrate), tablet (vitamin sodium), oral administration (vitamin E) tablet (vitamin E), vitamin E (vitamin E) and vitamin E (vitamin E) salts), vitamin E (vitamin E) and vitamin E (E) salts), vitamin E (E) and E) salts), vitamin E (E) and E (E) salts), vitamin E (E) and E (E) and E) salts), vitamin E (, Abiraterone acetate (azuratone acetate) (Zytiga), lutetium 177 dolatate (lutetium Lu 177 dottate) (LUTATHERA), afatinib (Gilotrif), olaparib tablet (olaparib tablets) (olaparib (Lynparza)), Pertuzumab (PERJETA), bosutinib (bosutinib) (BOSULIF), cabozantinib (cabozantinib, Cabometyxyx), Augivril (Ogivril) (Trastuzumab-dQot), sunitinib (sunitinib), obitudinuzumab (obib) (GAZYVA), Eimelizumab-IBkXE (HEMLHEMLE), Dasatinib (calcium) (Calibrutinib) (Calibritunib), Abilon (Abiranib) (ALB), Abiranib (L E (L), Abiranib (L) (L E (L), Abiranib (L, Abelib) (L), Abelib (E (L) (Calibritunib) (L (E) (L E (E), Abelib) (L (E, E (E) (L) (E) (L) (E) (L) and E (E) (L) (E) of Ab (E, E (E) of Ab (E, E (E) of Ab (E) of Ab, Mvasil (bevacizumab-awwb), gemtuzumab ozogamicin (gemtuzumab ozogamicin) (mylotar (Mylotarg)), ibritumomab ozogamicin (inotuzumab ozogamicin) (bespionsa), liposome-encapsulated daunorubicin in combination with cytarabine (lipome-encapsulated daunorubicin and cytarabine) (VYXEOS), ibrutinib (ibrutinib/ibruverica), enzidipine (IDHIFA), neratinib (NERLYNX), Betrixaban (BEVXXA), darifenanib and troglitinib (TAFIAR and MEKINIST), rituximab and human hyaluronidase (toxiximab and xauracil) (RINITIN), acetyl-arginine (aspirin (IBRIVIGAI), non-glucuronib (Acuminiba), non-glucuronidase (Acuminiba) (APRIVIRU), non-glucuronib (Avibritunib (SAI), non-citrate (SAL) (VeIl (SAI), non-glucuronib (SAL) (SAL-A), non-glucuronidase (SAL) (SAL-A), non-L-VICIRIVICII (SAL-A), non-L-A), SAL (SAL-E (SAL-A), SAL-E (SAL-R (SAL-E (SAL-R-E, SAL-E (SAL-E, SAL-E (SAL-E) (SAL-E, SAL-E (SAL-E) (, Nilapanib (zearib) (ZEJULA), aviluzumab (bavenciio), regoracil (kisquali), lenalidomide (rivlimide), lucakapanib (rubarca), daratumumab (daratumab) (DARZALEX), olaratumab (lartrruvo), aleuzumab (atezolizumab) (TECENTRIQ), erlotinib (TARCEVA), cabozantinib (cabomoteyx), defibrotide sodium (defibrino), crizotinib capsule (crizotinib capsules) (crizotinib (xalkorori)), everolimus (Afinitor), eridolizus (avitilin) (halen), and combinations thereof.
In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof; and at least one anti-cancer agent comprising one or more of: elobizumab (eltuzumab) (EMPLICITI), nimotuzumab (necitumumab) (PORTRAZZA), isoxazomib (NINLARO), cobimetinib (cobimetinib) (COTELLIC tablet), talimuira rappel (talimogene laherepec) (IMLYGIC), trabectedin (trabectedin Injection), irinotecan lipid Injection (onikyde), idarubizumab (idarubizumab) (Praxbind Injection), trifluridine/dipivelin (trifluridine/tipiracil) (lonnsurf), carfilzomib (carfilzomib/kyrolis), nide (sonigibuzumab) (doxycycline capsule (oxdoliz)), rituximab (doxycycline/capram) (zerumab (r), rit (r), rituximab (r), and (r-bizib) (sorafenib (r capsule (oxpain-r), and (r-bizizomib (r), and (r-bizizan (r) capsules (rypsin (r) (rypsin (r)) and (rypsin (r (rypsin) and (rypsin (r) of) Lanreotide (lanreotide acetate long-acting Injection (somataltine Depot Injection), ruxolitinib (ruxolitinib/Jakafi), Bornauzumab (BLINCYTO), idelalisib (idelalisib) (zoledrib tablet), belinostat (belinostat), mercaptopurine (mercaptoprine/Purixan), siuximab (siluximab) (silvard Injection (sylvestion)), ofatumumab) (orubin Injection (olarynl Injection)), oxfordimab (ofatumumab) (orubin Injection (arzepinoininjection)), nexaglib (NEXAVAR tablet), crizofurobile (nevavir Injection), oxsultaine (brevix Injection), oxsultaine (berrubicin Injection), paclitaxel (oxsultaine Injection (berrubicin Injection), paclitaxel (oxsultaine (berrubicin Injection), paclitaxel (abridarubicin (r Injection (berrubicin Injection), paclitaxel (abriazolirtin (r Injection), paclitaxel (oxsultaine (r Injection), paclitaxel (abricotina (r) and paclitaxel (oxsultaine (r (loxacin (r) Injection), paclitaxel (paclitaxel Injection), paclitaxel (oxsultaine (abriacum Injection), paclitaxel (abricotina (lox) and paclitaxel) Injection), paclitaxel (paclitaxel) and paclitaxel (paclitaxel Injection (paclitaxel) combined with paclitaxel (paclitaxel) Injection), paclitaxel (, Trastuzumab-maytansine conjugate (ado-trastuzumab emtansine) (KADCYLA for injection), pomalidomide (pommadomide capsule), doxorubicin hydrochloride liposome injection (doxorubicin hydrochloride liposome injection), and combinations thereof.
Examples of suitable anti-cancer agents include those described in: the pharmacological basis for the therapeutics of Goldmann and Gilman, 12 th edition, edited by Laurence Brunton, Bruce Chabner, Bjorn Knollman, McGro-Hill professional publishing Co., 2010.
In some exemplary embodiments, the pharmaceutical composition comprises a salt (e.g., a mono-or di-salt) of an emiperidone (e.g., ONC201) or analog thereof and at least one other therapeutic agent, wherein the other therapeutic agent includes an anti-angiogenic agent, e.g., bevacizumab. In one embodiment, the anti-angiogenic agent is selected from the group consisting of: abiracetin, axitinib, angiostatin, endostatin, a l6kDa prolactin fragment, laminin peptide, fibronectin peptide, tissue metalloproteinase inhibitor (
The pharmaceutical combination may comprise the first therapeutic agent and the second therapeutic agent in any desired ratio, as long as a synergistic or cooperative effect still occurs. The ratio of the first therapeutic agent to the second therapeutic agent of the synergistic pharmaceutical combination is preferably from about 1:9 to about 9: 1. In one embodiment, the ratio of the synergistic combination of the first therapeutic agent and the second therapeutic agent is from about 1:8 to about 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2: 1. In one embodiment, the ratio of synergistic combination therapeutic agents is about 1: 1.
In one embodiment, the second therapeutic agent is selected from the following: allopurinol, arsenic trioxide, azacitidine, bortezomib, bevacizumab, capecitabine, carboplatin, celecoxib, chlorambucil, clofarabine, cytarabine, dacarbazine, daunorubicin HCl, docetaxel, doxorubicin HCl, floxuridine, gemcitabine HCl, hydroxyurea, ifosfamide, Imatinib Mesylate (Imatinib Mesylate), ixabepilone, lenalidomide, megestrol acetate, methotrexate, mitotane, mitoxantrone HCl, oxaliplatin, paclitaxel, Pralatrexate (Pralatrexate), Romidepsin (Romidepsin), sorafenib, streptomycin, Tamoxifen Citrate (Tamoxifen cite), topotecan HCl, tretinoin, Vandetanib (Vandetanib), gemfibrodigimod (vismodegeigeb), vorinose (voostat), and combinations thereof.
In one embodiment, the second therapeutic agent comprises a small molecule multi-kinase inhibitor, e.g., sorafenib or regorafenib. In one embodiment, the second therapeutic agent comprises a hedgehog pathway inhibitor, e.g., vismodegib. In one embodiment, the second therapeutic agent comprises a drug selected from table 2 below.
Table 2: classes of drugs
In one embodiment, the second therapeutic agent comprises a drug that targets a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor. In one embodiment, the second therapeutic agent comprises a recombinant TRAIL or agonist antibody that activates one or more TRAIL receptors. In one embodiment, the second therapeutic agent comprises one or more antibodies or recombinant TRAIL that activates signaling of DR4, DR5, or both. In one embodiment, the second therapeutic agent comprises one or more of: AMG-655, LBY-135, mapatumab (mapatumumab), lexamumab (lexatumumab), Apocynum venetum (Apobab) and rhApo 2L/TRAIL. In one embodiment, the second therapeutic agent comprises an active agent selected from the group consisting of: camptothecin, 5-FU, capecitabine, cisplatin, doxorubicin, irinotecan, paclitaxel, cisplatin, bortezomib, BH3I-2, rituximab, radioactivity, triterpenes (triterpenoids), sorafenib, gemcitabine, HDAC inhibitors, carboplatin, T-101 (gossypol derivants), ABT-263, ABT-737 and GX-15-070 (olbacrat), vorinostat, cetuximab, panitumumab, bevacizumab, ganitumomab, interferon gamma, sorafenib, XIAP antagonists, Bcl-2 antagonists, and Smac mimetics.
Dosage VI
In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof in the following dosage ranges: about 40, 50, 60, or 100mg to about 2000 mg; about 4, 5, 6, or 10mg to about 200 mg; from about 0.4, 0.5, 0.6, or 1mg to about 20mg, wherein the weight may be based on the compound in its free base form. In one embodiment, the pharmaceutical composition comprises emilienone (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof at the following dosage level ranges: about 50mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; from about 5mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, and 200 mg; or from about 0.5mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 mg. In one embodiment, the pharmaceutical composition comprises emilienone (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof at the following dosage level ranges: about 40mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; about 4mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about 0.4mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 mg. In one embodiment, the pharmaceutical composition comprises emilienone (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof at the following dosage level ranges: from about 60mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; about 6mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about 0.6mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. In one embodiment, the pharmaceutical composition includes the following dosage levels ranges of emiliene (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof, based on the compound in its free base form: about 100mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900mg or 2000 mg; about 10mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about 1mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. In one embodiment, the pharmaceutical composition comprises emilienone (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof at the following dosage level ranges: from about 200mg to about 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; about 20mg to about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about 2mg to about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. In one embodiment, the pharmaceutical composition includes the following dosage levels ranges of emiliene (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof, based on the compound in its free base form: about 400mg to about 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; about 40mg to about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about 4mg to about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. In one embodiment, the pharmaceutical composition comprises emilienone (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof at the following dosage level ranges: about 50mg to about 60, 70, 80, 90 or 100 mg; about 60mg to about 70, 80, 90 or 100 mg; about 70mg to about 80, 90 or 100 mg; about 80mg to about 90 or 100 mg; about 90mg to about 100 mg; about 5mg to about 6, 7, 8, 9, or 10 mg; about 6mg to about 7, 8, 9, or 10 mg; from about 7mg to about 8, 9 or 10 mg; about 8mg to about 9 or 10 mg; about 9mg to about 10 mg; about 0.5mg to about 0.6, 0.7, 0.8, 0.9, or 1 mg; about 0.6mg to about 0.7, 0.8, 0.9, or 1 mg; about 0.7mg to about 0.8, 0.9, or 1 mg; about 0.8mg to about 0.9 or 1 mg; or from about 0.9mg to about 1 mg.
In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof in the following dosage ranges: about 1mg/kg to about 40 mg/kg; about 0.1mg/kg to about 4 mg/kg; or from about 0.01mg/kg to about 0.40 mg/kg. In one embodiment, the pharmaceutical composition comprises emilienone (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof at the following dosage level ranges: from about 1, 2, 3, 4, 5, 6, 7, 8, or 9mg/kg to about 10, 20, 30, or 40 mg/kg; from about 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19mg/kg to about 20, 30, or 40 mg/kg; from about 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29mg/kg to about 30 or 40 mg/kg; about 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39mg/kg to about 40 mg/kg; about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9mg/kg to about 1, 2, 3, or 4 mg/kg; from about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 or 1.9mg/kg to about 2, 3 or 4 mg/kg; about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, or 2.9mg/kg to about 3 or 4 mg/kg; or from about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, or 3.9mg/kg to about 4 mg/kg; about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09mg/kg to about 0.10, 0.20, 0.30, or 0.40 mg/kg; about 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, or 0.19mg/kg to about 0.20, 0.30, or 0.40 mg/kg; from about 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, or 0.29mg/kg to about 0.30 or 0.400. mg/kg; or from about 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, or 0.39mg/kg to about 0.40 mg/kg.
In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof in the following dosage ranges: about 37.5mg/m2To about 1500mg/m2(ii) a About 3.75mg/m2To about 150mg/m2(ii) a Or about 0.4mg/m2To about 15mg/m2. In one embodiment, the pharmaceutical composition comprises an emiperidone (e.g., ONC201) or analog thereof or a pharmaceutically acceptable salt thereof in the following dosage ranges: about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 525, 530, 540, 150, 155, 160, 165, 170, 195,545、550、555、560、565、570、575、580、585、590、595、600、605、610、615、620、625、630、635、640、645、650、655、660、665、670、675、680、685、690、695、700、705、710、715、720、725、730、735、740、745、750、755、760、765、770、775、780、785、790、795、800、805、810、815、820、825、830、835、840、845、850、855、860、865、870、875、880、885、890、895、900、905、910、915、920、925、930、935、940、945、950、955、960、965、970、975、980、985、990、995、1000、1005、1010、1015、1020、1025、1030、1035、1040、1045、1050、1055、1060、1065、1070、1075、1080、1085、1090、1095、1100、1105、1110、1115、1120、1125、1130、1135、1140、1145、1150、1155、1160、1165、1170、1175、1180、1185、1190、1195、1200、1205、1210、1215、1220、1225、1230、1235、1240、1245、1250、1255、1260、1265、1270、1275、1280、1285、1290、1295、1300、1305、1310、1315、1320、1325、1330、1335、1340、1345、1350、1355、1360、1365、1370、1375、1380、1385、1390、1395、1400、1405、1410、1415、1420、1425、1430、1435、1440、1445、1450、1455、1460、1465、1470、1475、1480、1485、1490、1495mg/m2To about 1500mg/m2(ii) a About 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 119, 115, 113, 112, 113, 125, 124, 121, 126, 121, 124, 121, 126, 121, 23, 132. 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 1 47. 148 or 149mg/m2To about 150mg/m2(ii) a Or about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 111, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5mg/m2To about 15mg/m2。
Formulation of the formula
The pharmaceutical compositions used in the methods described herein are formulated into dosage forms that can be administered to a patient. In one embodiment, the composition is in the form of an oral or parenteral dosage unit. In one embodiment, it is in the form of an oral dosage unit. In one embodiment, the oral dosage unit is fractionated into several smaller doses that are administered to the subject over a predetermined period of time to reduce the toxicity of the administered therapeutic agent. In one embodiment, the oral dosage unit is administered as a tablet or capsule comprising a controlled release formulation, which may comprise a plurality of granules, pills, mini-tablets or tablets. In some cases, the compositions are in the form of a parenteral dosage unit. For example, the parenteral dosage unit is selected from Intravenous (IV), Subcutaneous (SC) and intramuscular (M), rectal (PR) or transdermal. In one embodiment, the dosage form is selected from the group consisting of sterile solutions, suspensions, suppositories, tablets and capsules. In one embodiment, the oral dosage form is selected from the group consisting of tablets, caplets, capsules, lozenges, syrups, liquids, suspensions, and elixirs. In one embodiment, the oral dosage form is selected from the group consisting of tablets, hard shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids, and semisolids.
In one embodiment, the pharmaceutical composition used in the methods described herein comprises a dermatological composition suitable for topical application to the skin. For example, the dermatological composition comprises a pharmaceutically or cosmetically acceptable medium. Dermatological compositions for topical administration include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. In some cases, it may be necessary or desirable and therefore conventional pharmaceutical carriers (aqueous, powder or oily bases, skin enhancers, thickeners) are used. Suitable reinforcing agents include ethers, for exampleFor example, diethylene glycol monoethyl ether (asObtained) and diethylene glycol monomethyl ether; surfactants, for example, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, poloxamers (231, 182, 184), tweens (20, 40, 60, 80), and lecithin; alcohols, for example, ethanol, propanol, octanol, benzyl alcohol; polyethylene glycols and esters thereof, for example, polyethylene glycol monolaurate; amides and other nitrogen-containing compounds, for example, urea, 2-pyrrolidone, l-methyl-2-pyrrolidone, Dimethylacetamide (DMA), Dimethylformamide (DMF), ethanolamine, diethanolamine, and triethanolamine; a terpene; alkanones (alkanones); and organic acids, particularly citric acid and succinic acid. Can also use And sulfoxides, e.g., DMSO and C ι 0MSO, but less preferred.
In one embodiment, the dosage form is selected from the group consisting of sustained release, controlled release, delayed release, and responsive release.
VIII. method of use
The compositions and methods described herein have utility in treating a number of disease conditions including cancer (e.g., colorectal cancer, brain cancer, and glioblastoma). In one embodiment, the compositions and methods described herein are used to treat diseases such as ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomengial (leptomengial) disease, diffuse large B-cell lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendiceal cancer, astrocytoma, and atypical teratoid/rhabdoid tumor. In one embodiment, the compositions and methods described herein are used to treat diseases such as basal cell carcinoma, basal cell Nevus Syndrome, Guillain-Nevus Syndrome (Gorlin-Nevus Syndrome), bile duct cancer, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt's Lymphoma (Burkitt Lymphoma), and spinal cord tumors. In one embodiment, the compositions and methods described herein are used to treat diseases such as carcinoid tumors, primary unknown tumors, central nervous system atypical teratoid/rhabdoid tumors, leptomeningeal diseases, central nervous system embryonal tumors, central nervous system lymphomas, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, and cutaneous T-cell lymphoma (including Sezary syndrome and Mycosis Fungoides (MF)). In one embodiment, the compositions and methods described herein are used to treat diseases such as embryonic tumors of the central nervous system, endometrial cancer, ependymoma, esophageal cancer, ewing's sarcoma family, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, and ocular cancer (including intraocular melanoma and retinoblastoma). In one embodiment, the compositions and methods described herein are used to treat diseases such as gallbladder cancer, Gastric (Gastric/Stomach) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, and gliomas. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of: hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, histiocytosis, hodgkin lymphoma and hypopharyngeal cancer. In one embodiment, the compositions and methods described herein are used to treat diseases such as kaposi's sarcoma and renal (renal cell) cancer. In one embodiment, the compositions and methods described herein are used to treat diseases such as langerhans cell histiocytosis, laryngeal, lip and oral cancer, liver cancer, lung cancer (including non-small cell lung cancer and small cell lung cancer), non-hodgkin's lymphoma, and primary central nervous system lymphoma. In one embodiment, the compositions and methods described herein are used to treat diseases such as waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), malignant fibrous histiocytoma and osteosarcoma of bone, medulloblastoma, medullary epithelioma, melanoma, merkel cell carcinoma, mesothelioma, primary focally occult Metastatic cervical Squamous cell carcinoma (metastic squamocus Cancer with occult papillomary), multiple endocrine tumor syndrome, oral Cancer, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, complex karyotype, acute phase leukemia (blast phase leukemia), myelodysplastic/myeloproliferative tumors, multiple myeloma, and myeloproliferative disorders. In one embodiment, the compositions and methods described herein are used to treat cancer. In one embodiment, the compositions and methods described herein are used to treat diseases such as nasal and paranasal sinus cancer, nasopharyngeal cancer, and neuroblastoma. In one embodiment, the compositions and methods described herein are used to treat diseases such as oral cancer, lip and mouth cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer, and ovarian low-grade potential malignancy. In one embodiment, the compositions and methods described herein are used to treat diseases such as pancreatic cancer, papillomatosis, paranasal sinuses and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, intermediate pineal parenchymal tumors, pineal cytoma and supratentorial primitive neuroectodermal tumors, pituitary tumors, pleuropulmonary blastoma, pregnancy and breast cancer, primitive central nervous system lymphoma, and prostate cancer. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of: rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter cancer, Respiratory Tract cancer (Respiratory Tract cancer) involving the NUT Gene on
Compound (1) (ONC201) has broad anticancer activity, low toxicity (including few side effects, if any), low genotoxicity, and high bioavailability including oral bioavailability in vitro models, animal models, and human clinical trials. These features allow the ONC201 and various analogs to be particularly suitable for pediatric patients. These features also make ONC201 and various analogs particularly suitable for chronic therapy, high risk patients, and ensure long-term response or stabilize the disease or prevent disease recurrence.
In another aspect, provided herein is a method of treating or preventing cancer in a subject in need thereof, the method comprising: administering to said subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of compound (1)
Or a pharmaceutically acceptable salt thereof, wherein the cancer involves the midline structure of the brain and has a histone H3K27M mutation. In one embodiment, the cancer involves the thalamus, hypothalamus, basal ganglia, pineal gland, midbrain, cerebellum, pons, spinal cord or medulla. In one embodiment, the cancer is not a spinal cord tumor. In one embodiment, the histone H3K27M mutation is H3.3K 27M or H3.1K 27M. In one embodiment, the histone H3K27M mutation is in one or more histone genes selected from the group consisting of: H3F3A, H3F3B, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, or HIST1H 3J. In one embodiment, in cancer tissue, DRD2 is overexpressed, DRD5 is underexpressed, or both. In one embodiment, the subject is a human. In one embodiment, the subject is a domestic pet. In one embodiment, the subject is a pediatric subject.
In another aspect, provided herein is a method of treating or preventing cancer in a subject in need thereof, the method comprising: administering to the subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (10) or an analog or pharmaceutically acceptable salt thereof, wherein the cancer has a histone H3 mutation. In one embodiment, the cancer is selected from the group consisting of: central nervous system tumors, brain tumors, peripheral nervous system tumors, pheochromocytoma, paraganglioma, adrenocortical carcinoma, adrenal tumors, and neuroendocrine tumors. In one embodiment, the cancer is from a glial cell and is selected from the group consisting of: meningioma, ependymoma, oligodendroglioma, astrocytoma, optic glioma, pinealoma, rhabdoid tumor, and diffuse endogenous pontine glioma. In one embodiment, the cancer is from a neural cell and is selected from the group consisting of: medulloblastoma, neuroblastoma, ganglioneuroma, primitive neuroectodermal tumors, and schwannoma. In one embodiment, the cancer involves the thalamus, hypothalamus, basal ganglia, pineal gland, midbrain, cerebellum, pons, spinal cord or medulla. In one embodiment, the histone H3 mutation is H3.3K 27M or H3.1K 27M. In one embodiment, the K27M mutation of the cancer is in one or more histone genes selected from: H3F3A, H3F3B, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, or HIST1H 3J. In one embodiment, in cancer tissue, DRD2 is overexpressed, DRD5 is underexpressed, or both. In one embodiment, the compound is ONC 201. In one embodiment, the subject is a human. In one embodiment, the subject is a domestic pet. In one embodiment, the subject is a pediatric subject.
In another aspect, provided herein is a method of treating or preventing cancer in a subject in need thereof, the method comprising: administering to the subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (10) or an analog or pharmaceutically acceptable salt thereof, wherein the cancer involves the midline structure of the brain. In one embodiment, the cancer involves the thalamus, hypothalamus, basal ganglia, pineal gland, midbrain, cerebellum, pons, spinal cord or medulla. In one embodiment, the cancer is not a spinal cord tumor. In one embodiment, the cancer has a histone H3 mutation, wherein the histone H3 mutation is H3.3K 27M or H3.1K 27M. In one embodiment, the cancer has a histone H3K27M mutation in one or more histone genes selected from: H3F3A, H3F3B, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, or HIST1H 3J. In one embodiment, in cancer tissue, DRD2 is overexpressed, DRD5 is underexpressed, or both. In one embodiment, the compound is ONC 201. In one embodiment, the subject is a human. In one embodiment, the subject is a domestic pet. In one embodiment, the subject is a pediatric subject.
In one embodiment, the compositions and methods described herein are used to treat pediatric cancers (e.g., pediatric solid tumors, pediatric sarcomas, pediatric ewing's sarcoma, pediatric gliomas, pediatric central nervous system cancers, pediatric neuroblastoma, pediatric leukemias, and pediatric lymphomas).
In one embodiment, the compositions and methods described herein are used to treat proliferative skin disorders such as psoriasis. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of: salivary gland carcinoma, sarcoma, sezarin syndrome, Skin Cancer (Skin Cancer), eye Cancer, Skin Cancer (SkinCarcinoma), small intestine Cancer, soft tissue sarcoma, squamous cell carcinoma, primary foci occult neck squamous cell carcinoma, and supratentorial primary neuroectodermal tumors. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of: t cell lymphoma, testicular cancer, throat cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, and gestational trophoblastic tumor. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of: tumors of Unknown Primary focus (Carcinoma of Unknown Primary Site), cancers of Unknown Primary focus (Cancer of Unknown Primary Site), rare childhood cancers, transitional cell Carcinoma of the renal pelvis and ureter, urethral Carcinoma and uterine sarcoma. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of: vaginal cancer and vulvar cancer. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of: wilms Tumor (Wilms Tumor) and female cancers.
In one embodiment, the compositions and methods described herein are used as a first line therapy (sometimes referred to as first line therapy). In one embodiment, the compositions and methods described herein are used as a second line therapy. In one embodiment, the compositions and methods described herein are used as a three-line therapy. In one embodiment, the compositions and methods described herein are used as rescue therapy. The term "rescue therapy" means that any regimen of therapeutic agent can be employed after the subject's initial treatment regimen fails or after the subject's condition has not responded to the initial treatment. In one embodiment, the compositions and methods described herein are used as rescue therapy. In one embodiment, the compositions described herein are used as rescue agents to counteract the effects of the initial treatment. In one embodiment, the compositions described herein are used as rescue agents for administration to subjects who are resistant to standard or initial treatment. In one embodiment, the compositions and methods described herein are used as neoadjuvant therapy. In one embodiment, neoadjuvant therapy comprises administering one or more of the therapeutic agents described herein to a subject prior to mainline or first line therapy. In one embodiment, neoadjuvant therapy reduces the size or extent of the cancer treated prior to administration of primary or first line therapy to the subject undergoing treatment. In one embodiment, the compositions and methods described herein are used as an adjunct therapy. In one embodiment, adjuvant therapy comprises administering one or more therapeutic agents described herein to a subject, wherein the one or more therapeutic agents modify the effect of other therapeutic agents that have been administered to the subject either simultaneously with or subsequently to the subject.
In one embodiment, the compositions and methods described herein exhibit a reduced chance of drug-drug interaction. In one embodiment, the eliminatone (e.g., ONC201) or an analog thereof is eliminated from the patient before the eliminatone can interact with another pharmaceutically active agent.
In one embodiment, the compositions and methods described herein are shown to promote toxicity levels in combination with other pharmaceutical agents.
The compositions and methods described herein are not limited to a particular animal species. In one embodiment, a subject treated according to the methods described herein and using the compositions described herein can be a mammal or a non-mammal. In one embodiment, a mammalian subject includes, but is not limited to, a human; a non-human primate; rodents, such as mice, rats or guinea pigs; domestic pets such as cats or dogs; horse, cow, pig, sheep, goat or rabbit. In one embodiment, the non-mammalian subject includes, but is not limited to, an avian species, such as a duck, goose, chicken, or turkey. In one embodiment, the subject is a human. In one embodiment, the subject may be of any gender and any age. The compositions and methods may also be used to prevent cancer. The compositions and methods may also be used to stimulate the immune system.
The compositions and methods described herein are not limited to subjects of a particular age. In one embodiment, a subject treated according to the methods described herein and using the compositions described herein is over 50 years old, over 55 years old, over 60 years old, or over 65 years old. In one embodiment, a subject treated according to the methods described herein and using the compositions described herein is under 50 years of age, under 55 years of age, under 60 years of age, or under 65 years of age
. In one embodiment, the subject treated according to the methods described herein and using the compositions described herein is a pediatric patient. In one embodiment, the pediatric patient is less than 18 years old, less than 17 years old, less than 16 years old, less than 15 years old, less than 14 years old, less than 13 years old, less than 12 years old, less than 11 years old, less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, less than 2 years old, less than 1 year old. In one embodiment, the pediatric patient is less than 12 months old, less than 11 months old, less than 10 months old, less than 9 months old, less than 8 months old, less than 7 months old, less than 6 months old, less than 5 months old, less than 4 months old, less than 3 months old, less than 2 months old, less than 1 month old. In one embodiment, the pediatric patient is less than 4 weeks old, less than 3 weeks old, less than 2 weeks old, less than 1 week old. In one embodiment, the pediatric patient is less than 7 days old, less than 6 days old, less than 5 days old, less than 4 days old, less than 3 days old, less than 2 days old, or less than 1 day old. In one embodiment, the pediatric patient is a neonate. In one embodiment, the pediatric patient is a premature infant.
In one embodiment, the patient weighs less than 45kg, less than 40kg, less than 35kg, less than 30kg, less than 25kg, less than 20kg, less than 15kg, less than 14kg, less than 10kg, less than 5kg, less than 4kg, less than 3kg, less than 2kg, or less than 1 kg.
In one embodiment, the subject has received at least one past therapeutic agent. In one embodiment, the subject has received at least two, at least three, or at least four past therapeutic agents. In one embodiment, the previous therapeutic agent is ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunomycin, vincristine, prednisone, cytarabine, cisplatin, rituximab, 5-fluorouracil, oxaliplatin, folinic acid, or lenalidomide.
In one embodiment, the subject has undergone radiation therapy. In one embodiment, the subject has undergone surgical treatment. In one embodiment, the subject has been treated with adoptive T cell therapy.
In one embodiment, the cancer no longer responds to treatment with: ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunomycin, vincristine, prednisone, cytarabine, cisplatin, rituximab, 5-fluorouracil, oxaliplatin, folinic acid or lenalidomide, radiation, surgery or a combination thereof.
In one embodiment, the dose-response relationship of the compositions and methods described herein in cancer cells is different from the dose-response relationship of the same compositions and methods in normal cells. The dose response relationship of ONC201 to proliferation and cell death in normal and tumor cells was determined by measuring
In one embodiment, the compositions and methods described herein can be used to treat cancer in a subject. In one embodiment, the compositions and methods described herein can be used to treat cancer in a human subject. In one embodiment, the method of treatment comprises administering to a subject in need of such treatment a pharmaceutically effective amount of emilienone (e.g., ONC201) or an analog or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In one embodiment, the method of treatment comprises administering to a subject in need of such treatment: (i) a first therapeutic agent comprising an emiperidone (e.g., ONC201) or an analog thereof or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent in combination, wherein the first and second therapeutic agents are administered simultaneously or sequentially. The second therapeutic agent can be any suitable therapeutic agent, including pharmaceutically active agents disclosed herein. The pharmaceutically acceptable salts of ONC201 include the following dihydrochloride salts:
it is understood that the dihydrochloride salt of ONC201 or its analogs (including the compound of formula (10)) or alternative dihydrochloride thereof as would be apparent from the teachings of this disclosure may be substituted with ONC201 or its analogs in the compositions or dosing regimens described herein.
In one embodiment, the method of treatment comprises administering to a subject in need of such treatment, simultaneously or sequentially, a synergistic pharmaceutical combination, wherein the synergistic pharmaceutical combination comprises (i) a first therapeutic agent comprising an emiperidone (such as ONC201) or an analog thereof or a pharmaceutically acceptable salt thereof; and (ii) a second therapeutic agent. In one embodiment, the method of treatment comprises administering to a subject in need of such treatment, simultaneously or sequentially, a therapeutically synergistically effective amount of a combination of the first therapeutic agent and the second therapeutic agent. In one embodiment, the method of treatment comprises administering to a subject in need of such treatment an effective amount of a combination of the first therapeutic agent and an effective amount of the second therapeutic agent, wherein the combination provides a synergistic effect in the in vivo treatment of a cancer sensitive to the combination, and wherein the first therapeutic agent and the second therapeutic agent are administered simultaneously or sequentially. In one embodiment, the method of treatment comprises administering to a subject in need of such treatment an effective amount of a combination of the first therapeutic agent and an effective amount of the second therapeutic agent, wherein the combination provides a synergistic effect in the in vivo treatment of minimal residual disease susceptible to the combination, and wherein the first therapeutic agent and the second therapeutic agent are administered simultaneously or sequentially. In one embodiment, the second agent is administered prior to the first agent.
In one embodiment, the treatment targets a cancer selected from the group consisting of: solid tumors, liquid tumors, lymphomas, leukemias, or myelomas.
In one embodiment, the treatment targets a solid tumor, wherein the solid tumor is selected from the group consisting of: cervical cancer, endometrial cancer, extracranial germ cell tumors; gonadal ectogenital cell tumors; germ cell tumors; gestational trophoblastic tumors; ovarian cancer, ovarian germ cell tumors, ovarian epithelial cancer, and ovarian low-grade potential malignancies; penile cancer, prostate cancer; pregnancy and breast cancer; high grade prostate cancer; medium grade prostate cancer; low grade prostate cancer; castration resistant prostate cancer; breast cancer; bile duct cancer; extrahepatic bile duct cancer; gallbladder cancer; hepatocellular (liver) cancer; renal (renal cell) cancer; liver cancer, renal cell (renal) cancer, renal pelvis and ureteral cancer; basal cell carcinoma; basal cell nevus syndrome, Guillain-nevus syndrome, melanoma, Merkel cell carcinoma, papillomatosis, multiple endocrine tumor syndrome; pancreatic cancer, parathyroid cancer, ocular melanoma; eye cancer; retinoblastoma; malignant fibrous histiocytoma; the Ewing sarcoma family; desmoplastic round cell tumors; chondrosarcoma, kaposi's sarcoma, rhabdomyosarcoma; spinal cord tumors, leptomeningeal disorders, central nervous system embryonic tumors, chordoma, central nervous system embryonic tumors, ependymoma, neuroblastoma; mesodifferentiation pineal parenchymal tumors, pineal cytoma; adrenocortical carcinoma; bone cancer, osteosarcoma; malignant fibrous histiocytoma of bone and osteosarcoma; osteosarcoma and malignant fibrous histiocytoma of bone; carcinoid tumor, primary unknown tumor, bronchial tumor, lung cancer, pleuropulmonary blastoma; respiratory cancer, astrocytoma, atypical teratoid/rhabdoid tumor involving the NUT gene on chromosome 15; atypical teratoid/rhabdoid tumor of the central nervous system, craniopharyngioma, glioma, brain cancer, medulloblastoma, medullary epithelioma, supratentorial primitive neuroectodermal tumor; pituitary tumors; gastric (Gastric/Stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), bladder cancer, anal or rectal cancer, appendiceal cancer, esophageal cancer, hypopharyngeal cancer; laryngeal, lip and oral, primary occult metastatic squamous cell carcinoma of the neck, oral (Mouth Cancer), nasal and paranasal sinus Cancer, nasopharyngeal, oral (OralCancer), lip and oral, oropharyngeal, paranasal and nasal, pharyngeal Cancer; head and neck cancer and mesothelioma.
In one embodiment, the treatment targets a lymphoma selected from the group consisting of: diffuse large B-cell lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, sezary's syndrome, Mycosis Fungoides (MF); histiocytosis; burkitt's lymphoma and central nervous system lymphoma; non-hodgkin's lymphoma and primary central nervous system lymphoma, hodgkin's lymphoma, waldenstrom's macroglobulinemia; mycosis fungoides; primary central nervous system lymphoma; lymphoplasmacytic lymphoma and primary central nervous system lymphoma. In one embodiment, the treatment targets a non-hodgkin lymphoma, which non-hodgkin lymphoma (NHL) is selected from the group consisting of: mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, lymphoplasmacytic NHL, waldenstrom's macroglobulinemia, and cutaneous lymphoma.
In one embodiment, the method of treatment targets leukemia selected from the group consisting of: acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), chronic myeloproliferative disorders; hairy cell leukemia; acute Myeloid Leukemia (AML); chronic Myelogenous Leukemia (CML); and Langerhans cell histiocytosis. In one embodiment, the treatment targets an acute leukemia selected from the group consisting of: acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, and myeloproliferative disorders.
In one embodiment, the treatment targets a myeloma selected from the group consisting of: IgA myeloma; an IgG myeloma; an IgM myeloma; an IgD myeloma; IgE myeloma; a light chain myeloma; a non-secretory myeloma; complex karyotype, acute stage leukemia; multiple myeloma/plasma cell tumors, multiple myeloma, myelodysplastic syndrome, myelodysplastic/myeloproliferative tumors, and myeloproliferative disorders.
In some cases, the treatment targets a peripheral nervous system tumor. In some cases, the treatment targets paraganglioma. In some cases, the treatment targets pheochromocytoma.
In one embodiment, the treatment of cancer comprises preventing tumor growth in a cancer subject. In one embodiment, the treatment of cancer comprises preventing the formation of cancer metastases in a cancer subject. In one embodiment, the treatment of cancer comprises targeted treatment of minimal residual disease in a cancer subject known to have minimal residual disease in cancer or a subject at risk of having minimal residual disease.
This may be indicated after the primary tumor has been treated surgically and/or after chemotherapy (radiotherapy) has begun or been established to be effective. Disseminated tumor cells can be in their dormant state and often cannot be attacked by chemotherapy (radiotherapy). The patient so treated appears to be in a state of recovery and is referred to as "minimal residual disease". However, if dormant tumor cells become metastatic cells due to growth stimulation after a long dormant state, the dormant tumor cells are likely to form metastases.
The term "minimal residual disease" refers to a small number of cancer cells that remain in a subject during or after treatment when the subject's condition is alleviated (symptoms or signs of the disease are not shown). The methods described herein are preferably applied to the disease forms listed herein, including adult and pediatric forms of these diseases.
In one embodiment, the treatment method can be used to treat an autoimmune disease. Autoimmune diseases include, but are not limited to, alopecia areata, antiphospholipids, autoimmune hepatitis, celiac disease, type 1 diabetes, Graves 'disease, Guillain-Barre syndrome (Guillain-Barre syndrome), Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, inflammatory myopathy, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, sjogren's syndrome (sjogren's disease)
In one embodiment, the treatment method can be used to treat the following diseases: autoimmune and inflammatory disorders of the peripheral nervous system such as amyotrophic lateral sclerosis (Lou Gehrig's disease); disorders based on the following causes: such as metabolic disorders including diabetes, B12 and folate vitamin deficiencies, chemotherapeutic drugs and drugs for the treatment of HIV, poisons causing damage to peripheral nerves, cancers that progress to peripheral neuropathy and to paraneoplastic syndromes, alcohol abuse, chronic kidney disease, damage causing nerve compression and other pathologies; infections such as Lyme disease, Guillain-Barre syndrome, connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, etc.; certain inflammatory conditions such as sarcoidosis, celiac disease, and the like; hereditary diseases such as charcot marie syndrome (charcot marie tooth syndrome), friedreich's ataxia, and/or idiopathic diseases in which inflammatory and/or autoimmune mechanisms are causative although specific causes are not found.
In one embodiment, the treatment methods can be used to treat autoimmune and inflammatory disorders with clinical manifestations of the eye. Such ocular clinical manifestations include, but are not limited to, ocular cicatricial pemphigoid, rhetinic corneal ulceration (Mooren's corneal ulcer), various forms of uveitis, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, relapsing polychondritis, Wegener's granulomatosis, scleroderma, Behcet's disease, Reiter's disease, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and ankylosing spondylitis, retinitis pigmentosa, macular degeneration, keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, peripheral corneal ulceration, and uncommon entities such as choroidal macular sarcoidosis, retinal vasculitis, scleral sarcoidosis, retinal detachment, and/or edema.
In one embodiment, the treatment method can be used to treat acute allograft rejection in a transplant patient. In one embodiment, the treatment method can be used to treat ischemic stroke. In one embodiment, the treatment methods can be used to treat inflammatory diseases including arthritis, psoriasis, asthma, and colitis.
In one embodiment, the therapeutic agent comprises a pharmaceutically acceptable monosalt of ONC201 or an analog thereof (e.g., a compound of formula (10)). In one embodiment, the therapeutic agent comprises ONC201 dihydrochloride or an analog thereof (e.g., a compound of formula (10)). As described herein, some analogs can be trisalts. In one embodiment, the therapeutic agent comprises ONC201 or an analog thereof (e.g., a compound of formula (10)) in a pharmaceutically acceptable mono-or di-salt form selected from the group consisting of: hydrochloride, hydrobromide, bisulfate, sulfate, phosphate, fumarate, succinate, oxalate and lactate, acid sulfate, hydroxy salt, tartrate, nitrate, citrate, acid tartrate, carbonate, malate, maleate, fumarate sulfonate, methanesulfonate, formate acetate and carboxylate. In one embodiment, the therapeutic agent comprises ONC201 or an analog thereof in a pharmaceutically acceptable mono-or di-salt form selected from the group consisting of p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate, and maleate. In one embodiment, the therapeutic agent comprises ONC201 or an analog thereof in a pharmaceutically acceptable mono-or di-salt form having a counterion selected from the group consisting of: ammonium, sodium, potassium, calcium, magnesium, zinc, lithium and/or with the following counterions: such as methylamino, dimethylamino, diethylamino, and triethylamino counterions, and combinations thereof. In one embodiment, the therapeutic agent comprises a compound described herein in the form of a halogenated dihydrochloride salt (e.g., a dihydrochloride or a dihydrobromide salt).
In one embodiment, the second therapeutic agent comprises an anti-cancer agent. In one embodiment, the second therapeutic agent is selected from the following: acivicin, aclarubicin, acibenzolar, alcodazole, alclomezine, aldehydamine, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, amethrone, amifostine, aminoacridine, anastrozole, ampreomycin, arsenic trioxide, asparaginase, clindamin, azacitidine, azatepa, azomycin, batimastat, benztepa, bevacizumab, bicalutamide, bisantrene, bismuthate, bizelesin, bleomycin, brequina, bripirimid, busulfan, actinomycin, carpestosterone, capecitabine, cameramide, cabetimer, carboplatin, camostatin, cameracin, camaixorubicin, cyazosin, sildenafil, cisapride, cisplatin, cladribine, ractamide, cyclophosphamide, acyclorac, carbapenem, cadin, canafurazone, celadox, celecoxib, celadox, doxine, doxycycline, actinomycin, daunomycin, decitabine, dexomaplatin, dizuanine, dizangonine methanesulfonic acid, siluroquinone, docetaxel, doxorubicin, droloxifene, drotaandrosterone, dapzomycin, edatrexate, eflornithine, elsamitrucin, enloplatin, emprethane, epipiperidine, epirubicin, erbuzole, esorubicin, estramustine, etanidazole, etoposide, fazodan, fazarabine, veboxamide, floxuridine, fludarabine, fluorouracil, flurocitabine, fequinone, fostrexed, fulvestrant, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imofovir, interleukin II (IL-2, including recombinant interleukin II or rIL2), interleukin alpha-2 a, interleukin alpha-2 b, interleukin alpha-1, Interleukins alpha-n 3, interleukin beta-Ia, interleukin gamma-Ib, iproplatin, irinotecan, lanreotide, letrozole, leuprorelin, liarozole, lometrexol, lomustine, losoxanone, maxolone, maytansine, mechlorethamine hydrochloride, megestrol acetate, melphalan, menariel, mercaptopurine, methotrexate, chlorpheniramine, melutin, mitodomide, mitocaicin, mitoxamine, mitomycin, mitospertisin, mitotane, mitoxantrone, mycophenolic acid, nelarabine, nocodazole, nogalamycin, olmesalamine, oxsulam, paclitaxel, pemetrexenase, peimeriine, pentazocine, pezilin, phospholane, pipobroman, piripomoesin, pirimicin hydrochloride, melloporphan, mefenoporphycin, mefenoporphydrogen, mefenoporphycin, mefenoprofen, porphydroxyfolacin, porphin, and other pharmaceutically acceptable salts, Mitomycin, prednimustine, procarbazine, puromycin, pyrazolofuranin, libanosine, roglucimine, safagon, semustine, octreozine, aspartyl, sparmycin, gerospiramine, spiromustine, spiroplatinum, pronil, streptozotocin, sulfochlorpheniramine, talimycin, tamoxifen, tegolazine, tegafur, tilloanthraquinone, temoporphine, teniposide, tiroxepin, testolactone, thioprimine, thioguanine, thiotepa, thiazolecarboxamide nucleoside, tirapazamine, topotecan, toremifene, trotolterolone, triciribine, trimetrexate, triptorelin, tobuzole, uramustine, uretepa, vapreotide, vesper, vinblastine sulfate, vindesine, vinglycinate, vinorelbine, vinorelb, Vinzolidine, vorozole, zeniplatin, setastatin, zoledronic acid, zorubicin, and combinations thereof.
In one embodiment, the second therapeutic agent is selected from the following: hormone analogs and anti-hormones, aromatase inhibitors, LHRH agonists and antagonists, growth factor inhibitors, growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors; an antimetabolite; an anti-tumor antibiotic; a platinum derivative; an alkylating agent; an anti-mitotic agent; a tubulin inhibitor; PARP inhibitors, enzyme inhibitors, serine/threonine kinase inhibitors, tyrosine kinase inhibitors, protein-protein interaction inhibitors, MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogues, amifostine, aloglipde, Kludlarder, filgrastim, interferons, interferon alpha, folinic acid, rituximab, procarbazine, levamisole, mesna, mitotane, disodium and porfilline phosphate, 2-chlorodeoxyadenosine, 2-fluorodeoxy-cytidine, 2-methoxyestradiol, 2C4, 3-alexin, 131-1-TM-601, 3, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, Abiraterone, aldesleukin, alitretinoin, alovermectin-7, altretamine, alloxideb, amonafide, anthrapyrazole, AG-2037, AP-5280, apazione, apomorphine, alano, arglabin, azaciclovir, atamestan, atrasentan, orlistatin-PE, ABT-199 (von Willtork), ABT-263 (nextasx), AVLB, AZ10992, ABX-EGF, AMG-479 (Ganituzumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (ARRY 3544), ARRY-704/AZD-8330, AR-12, ARQ-42, AS-703988, AXL-1717, AZD-55, AZD-5363, AZD-680, 736-6244, ARRY-302706 (ARRx-703026), ARR-706 (ARRx-709 (Ganituzumab), ARRx-E), ARRY-479 (Galitumumab), Avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, Biercoda di-citric acid, BCX-1777, BKM-120, bleomycin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (afatinib, Tuotuka)), BIBF 1120 (Nindanib), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycin acid, bleomycin A, bleomycin B, brib, brimonib, timibo-1, borrelidin, bortezomib, borrelidin, bryonia CA-4 prodrug, CA-4, cap cell, calcitriol, canertinib, canfosfamide, capecitabine, carboplatin carboxyphthalate, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, homoharringtonine, ceftriaxone, celecoxib, simon, cimadotin, CH4987655/RO-4987655, clorenyl ether, cilansil, cyclosporine, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-tala, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, dactinomycin, arabinoside, D24851, Decitabine, deoxobixin, doxycycline, desoxyhelpicol, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflutecan, didocx, DMDC, urodoline 10, dorazozole, DS-7423, E7010, E-6201, edatrexate, an ehyprinol, eprocoxib, erlotinib, EGFR inhibitors, EKB-569, EKB-509, enzepine, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3, ethynylcytidine, ethinyl estradiol, irinotecan, exemestane, valacycline, getemab, floxuridine, folacin, FOLFOX, FOLF 4, FOIRI, FORTA, fosfomycin, GAMMA, maltofeitin, maltofexol, doxin, doxorubine, dT-B, dexgefitinib, edestin, ethi, Gemtuzumab ozogamicin, gemmacetan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (picosecond), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp 100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trimetinib), GSK-2118436 (dalafinil), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, 2016 GW, granisetron, herceptin, hexamethylpyrimethanil, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatramadol, estrenol, IDN-9, IGF-1R inhibitor, IMC-351R inhibitor, 11-85C-12 (Cetussi A), Immunology, Indusalam, interferon alpha-2 a, interferon alpha-2B, PEG interferon alpha-2B, Interleukin-2, INK-1117, INK-128, INSM-18, jonafamone, Yipriomam, Isoplatine, iloufen, Isohalomethocholic acid B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, carhalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lengstin, leuprolide, riobolin, Cedar, LGD-1550, linezolid, motoxafen, lometrexolone, loxoanthraquinone, LU, 223651, toltecan, LY-S6AKT1, LY-2780301, macrachloramide, malamida, MEK 162, MEK-162 inhibitor, MEK-162, and MEK-162, Methyl testosterone, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (Darlozumab), MLN518, motoxafen gadolinium, MS-209, MS-275, MX6, neridronic acid, neratinib, Nixsaval, cancerib, nilotinib, nimesulide, nitroglycerin, loratrexed, norlin, N-acetylcysteine, 06-benzyl guanine, obilison, omeprazole, conphenanthrene, tumors VEXGM-CSF, Omiplatin, Otacrine, OX44 antibody, OSI-027, OSI-906 (Risinetinib), 4-1BB antibody, losartan, estrogen, pannonib, Papirolone, PCK-3145, and Spanish-3145, Pefeungstic, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, bindrex, perimidicin, perillyl alcohol, pertuzumab, PI3K inhibitor, PI3K/mTOR inhibitor, PG-TXL, PG2, PLX-4032/RO-5185426 (vemounib), PLX-3603/RO-5212054, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, Pirenong, phenoxydiphenol O, PKI166, Pratriplex, plicamycin, polyglutamic acid, Methylsilubicin, PT-1402, prednisolone, quinine, Quedlerotinib, Podocarpine, PlFormica, Pythritol, PlIn-427, PlIn-3, PlTbx-3, Quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436, a butterfly mycin analog, a Receptor Tyrosine Kinase (RTK) inhibitor, thalidomide analog, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, lisoprotein, rhu-MAb, linfenofibrate, risedronate, rituximab, rofecoxib, RO-31-7453, RO-5126766, RO-50760, RPR 109881A, norbizide, rubitecan, R-flurbiprofen, RX-0201, S-9788, sarubicin, SAHA, sargrastim, satraplatin, SB 408075, Se-015/Ve-6616, SU5416, SU, SDX-101, semotoxin, Sesamotine, Sesamotirtin, Semiastin-11355, saratin-38, sarlittereol, alcohol, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, anilidohydroxamic acid, sotriptan, T900607, T138067, TAK-733, TAS-103, tacrine, talaporfin, Tarceva, Tarrexed, tasolan, taxotere, taxol, taxotene, tazarotene, flupyradine, temozolomide, timinafine, testosterone propionate, timinafine, tetraplatin, tetrodotoxin, tizacitabine, thalidomide, tyloxazuril, tetrahydropyrad doxorubicin, thymalfasin, thymosin, thiazolecarboxamide nucleoside, tipifarnib, ranitrexed, tizamine, tolazadine, trabexadine, MID-107, travefrin, tretinoin, tretinomycin, tremulin, tritrexate, TLK-286TXD258, texab (tykerb/tyverb), uracil, valrubicin, vartanib base, vincristine, vinflunine, vitamins such as ligin, WX-UK1, WX-554, panitumumab, Hirodad, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, 1839, ZSTK-474, sodium zoledronate, Azoquinad and combinations thereof.
In one embodiment, the second therapeutic agent is selected from the following: tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone, finasteride, buserelin acetate, fludrocortisone, flumetsterone, medroxyprogesterone, octreotide, and combinations thereof. In one embodiment, the second therapeutic agent is selected from LHRH agonists and LHRH antagonists. In one embodiment, the LHRH agonist is selected from goserelin acetate, lulanolide acetate, triptorelin pamoate, and combinations thereof. In one embodiment, the second therapeutic agent comprises an LHRH antagonist selected from the group consisting of: degarelix, cetrorelix, abarelix, ozagrick, degarelix, and combinations thereof. In one embodiment, the second therapeutic agent comprises a growth factor inhibitor. In one embodiment, the growth factor inhibitor is selected from the following inhibitors: platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF), Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER), Hepatocyte Growth Factor (HGF), and combinations thereof. In one embodiment, the human epidermal growth factor (HER) is selected from HER2, HER3, and HER 4.
In one embodiment, the second therapeutic agent comprises a tyrosine kinase inhibitor. In one embodiment, the tyrosine kinase inhibitor is selected from the group consisting of cetuximab, gefitinib, imatinib, lapatinib, and trastuzumab, and combinations thereof. In one embodiment, the second therapeutic agent is an aromatase inhibitor. In one embodiment, the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, liarozole, vorozole, exemestane, atamestan and combinations thereof.
In one embodiment, the second therapeutic agent is an antimetabolite. In one embodiment, the antimetabolite comprises an antifolate. In one embodiment, the antifolate is selected from the group consisting of methotrexate, raltitrexed, pyrimidine analogs, and combinations thereof. In one embodiment, the antimetabolite is a pyrimidine analog. In one embodiment, the pyrimidine analog is selected from the group consisting of 5-fluorouracil, capecitabine, gemcitabine, and combinations thereof. In one embodiment, the antimetabolite is a purine analog or an adenosine analog. In one embodiment, the purine analog or adenosine analog is selected from the group consisting of mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof. In one embodiment, the second therapeutic agent comprises an anti-tumor antibiotic. In one embodiment, the anti-tumor antibiotic is selected from the group consisting of anthracyclines, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, actinomycin, plicamycin, streptozotocin, and combinations thereof. In one embodiment, the second therapeutic agent comprises a platinum derivative. In one embodiment, the platinum derivative is selected from cisplatin, oxaliplatin, carboplatin, and combinations thereof. In one embodiment, the second therapeutic agent comprises an alkylating agent. In one embodiment, the alkylating agent is selected from the group consisting of estramustine, mechlorethamine hydrochloride, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, and combinations thereof. In one embodiment, the second therapeutic agent comprises a nitrosourea. In one embodiment, the nitrosourea is selected from carmustine, lomustine, thiotepa and combinations thereof. In one embodiment, the second therapeutic agent comprises an antimitotic agent. In one embodiment, the antimitotic agent is selected from vinca alkaloids and taxanes. In one embodiment, the taxane is selected from paclitaxel, docetaxel, and combinations thereof. In one embodiment, the vinca alkaloid is selected from the group consisting of vinblastine, vindesine, vinorelbine, vincristine, and combinations thereof. In one embodiment, the second therapeutic agent comprises a topoisomerase inhibitor. In one embodiment, the topoisomerase inhibitor is an epipodophyllotoxin. In one embodiment, the topoisomerase epipodophyllotoxin is selected from etoposide, valpiride, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, and combinations thereof. In one embodiment, the second therapeutic agent comprises a serine/threonine kinase inhibitor. In one embodiment, the serine/threonine kinase inhibitor is selected from the group consisting of a PDK 1 inhibitor, a B-Raf inhibitor, an mTOR inhibitor, an mTORC1 inhibitor, a PI3K inhibitor, a dual mTOR/PI3K inhibitor, an STK 33 inhibitor, an AKT inhibitor, a PLK 1 inhibitor, a CDK inhibitor, an aurora kinase inhibitor, and combinations thereof. In one embodiment, the second therapeutic agent comprises a tyrosine kinase inhibitor. In one embodiment, the second therapeutic agent comprises a PTK2/FAK inhibitor. In one embodiment, the second therapeutic agent comprises a protein-protein interaction inhibitor. In one embodiment, the protein-protein interaction inhibitor is selected from the group consisting of IAP, Mcl-1, MDM2/MDMX, and combinations thereof. In one embodiment, the second therapeutic agent comprises a rapamycin analog. In one embodiment, the rapamycin analog is selected from the group consisting of everolimus, temsirolimus, ridaforolimus, sirolimus, and combinations thereof. In one embodiment, the second therapeutic agent is selected from the group consisting of amifostine, argralide, croudalat, filgrastim, interferon alpha, folinic acid, rituximab, procarbazine, levamisole, mesna, mitotane, disodium pamidronate, and porfield sodium, and combinations thereof. In one embodiment, the second therapeutic agent is selected from the following: 2-chlorodeoxyadenosine, 2-fluorodeoxy-cytidine, 2-methoxyestradiol, 2C4, 3-alicine, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alistinoin, alovermectin-7, altretamine, alloxidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apazidone, apomorphine, aronostem, arglabin, azaciclib, atacetazone, atrasentan, orestatin-PE, ABT-199 (venetock), ABT-263 (nevetetos), Claritol, AZ10992, ABX-EGF, AMG-479 (cannibin), ARRY 162 RY 162, 2-methoxyestradiol, 2C4, 3-alicine, 3-Adelin, Arthromycin-7, altretamine, Alcalix-7, Aminolide, anthrax-5280, apomorphine, Alpint-E, Alpint-PE, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (semetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primimacetobu), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, bicitric acid bicitrate BCX-1777, BKM-120, bleomycin, BLP-25, BMS-184476, BMS-247550, BMS-27797, BMS-275291, BNP-663513, BMS-754807, BMS-7787, and pharmaceutically acceptable salts thereof, BIBW 2992 (afatinib, Turitovack)), BIBF 1120 (ninidanib), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycin acid, bleomycin A, bleomycin B, brimonib, bryodin-1, bortezomib, brezostorine, busulfan, BYL-719, CA-4 prodrug, CA-4, capping cells, calcitriol, canertinib, capecitabine, carboplatin carboxyphthalate, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 clocefixime, homoharringtonine, ceftriaxone, celecoxib, simons, cimadotin, CH 4987655/RO-874987655, clenbuterol, jeldahl, cecropin, ciclovir, cyclicin, CDCA-II, CDC-CDC, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-tylan, CMT-3 Nostoc 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247, phycotoxin doxorubicin, arabinoside, D24851, decitabine, desoxybixin, desoxyvivax, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflutecan, didocoris, DMDC, Dolaborin 10, dorazozole, DS-7423, E7010, E-6201, Adriant, epothilones, ethylpropylalone, Ennesie, EGFR inhibitors, EKB-569, EKB-509, Enzalin, Enzamide, Egyolb, Egylocin B, Epigosacin-4 monoclonal antibodies, CP-461, CV-247, Doxolone, Doxorubicin, Doxolone, Adenosine, Adriacin, ER-86526, erlotinib, ET-18-0CH3, ethynylcytidine, ethinyl estradiol, irinotecan methanesulfonic acid, exemestane, vemuramyl amine, feigimab, floxuridine, folic acid, FOLFOX4, FOLFIRI, formestane, fotemustine, doxorubicin, maltogallium, gefitinib, gemtuzumab ozolomide, gemmace, glufosfamide, GCS-100, GDC-0623, GDC-0941 (Picklesp), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp 100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-21136 (GSK-211643958, GSK-6458, GSK-64 2110183, GSK-6458, GSK-387, GSK-2141795, GW2016, granisetron, herceptin, hexamethopyrimine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab tiuxetan, edatrexate, estrenol, IDN-5109, IGF-1R inhibitor, IMC-1C11, IMC-A12 (Cetuzumab), immunology, Indexsuramel, interferon alpha 2a, interferon alpha 2B, peginterferon alpha 2B, interleukin-2, INK-1117, INK-128, INSM-18, jonatron, primomum, iproplatin, ifosfen, isohalomethocholic acid B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, carhalidride F, ketoconazole, KW-0, KW-KW 0, IfK-21783, conjugated estrogens, Icaribber, Iphiglim, Ipom, Ipombe, Lobaplatin, leflunomide, lengeritin, leuprorelin, riobolin, lesitedulonam, LGD-1550, linezolid, motaxafine lutetium, lometrexol, losoxantrone, LU 223651, lurotecan, LY-S6AKT1, LY-2780301, phosphoramide, marimastat, mechlorethamine, MEK inhibitor, MEK-162, methyltestosterone, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, mitotane, minodronic acid, mitomycin, mitobulin, MK-2206, MK-0646 (dallodolizumab), MLN518, motaxfene gadolinium, MS-209, MS-MX, MS-275, 6, neridronic acid, lenatinib, nikkalal, canvasal, nilotinib, sunitinib, glycerol, cysteine-N nitrate, acetyl-N-S6 AKT1, LY-D-, 06-benzylguanine, opilison, omeprazole, conphyte, tumor VEXGM-CSF, Omipiplatin, Otacrine, OX44 antibody, OSI-027, OSI-906 (Rivastigrinib), 4-1BB antibody, oxisartan azole, estrogen, panitumumab, palipiderone, pefilgrastim, PCK-3145, pefilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, Pedrix, perlixsin, perillyl alcohol, pertuzumab, PI3K inhibitor, PI 3K/TXJ inhibitor, PG-35L, PGS 2, PLX-RO-5185426 (Moffonil), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxydiphenol O, PKI166, plectrosterin, plicamycin, polyglutamic acid, methylmitomycin, prednisone, prednisolone, quinidine, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY869766, RDEA-436, a butterfly mycin analog, a Receptor Tyrosine Kinase (RTK) inhibitor, thalidomide analog, RG-7167, RG-7304, RG-7421, RG-7321, RG-7440, lisoprophos, rhu-MAb, linfelbinae, risedronate, rituximab, rofecoxib, felodib, RO-31-7453, RO-5126766, RO-50760, RPR-A, hydrazide A, and phenylbenzidine 10910910932, Rubitecan, R-flurbiprofen, RX-0201, S-9788, sarubicin, SAHA, sargrastim, satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-74317, SR-13668, SRL-172, sorafenib, spiroplatinum, squalamine, anilino hydroxamic acid, sotripan, T900607, T061387, TAK-733, TAS-103, tacrine, talaporfin, tarocaine, taraxolide, tasolazine, taxotere, tazarotene, tegafur, temozolomide, mirifen, testosterone propionate, tetrodotoxin, texol, tetaxane, tazarin, tazarotene, teflutazimine, texabexabexaparine, texabexaparine, Thymalfasin, thymosin, thiazolecarboxamide nucleoside, tipifarnib, tirapazamine, torasemide, raltitrexed, toremifene, trabectedin, trans MID-107, trans retinoic acid, trastuzumab, tremelimumab, retinoic acid, triacetyluridine, triazepine, tricitabine, tritrexate, TLK-286TXD258, tylobo (tykerb/tyverb), uracil, valrubicin, vartanainine, vincristine, vinflunine, vitamins such as lignt, WX-UK1, WX-554, panitumumab, Hiroandax, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-6173, ZD-6126-741, ZD-0473, ZD-1-741, ZD1839, ZSTK-474, sodium zoledronate, azaquinad, and combinations thereof.
In one embodiment, the other therapeutic agent comprises a steroid comprising dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cocazole. In one embodiment, the other therapeutic agent comprises an antiemetic agent. Antiemetics include, but are not limited to, 5-HT3 receptor agonists (e.g., dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine); dopamine agonists (e.g., domperidone, olanzapine, haloperidol, chlorpromazine, prochlorperazine, aripride, prochlorperazine, and metoclopramide); NK1 receptor antagonists (e.g., aprepitant and casotetherein); antihistamines (such as cyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine); cannabinoids (e.g., cannabis, dronabinol, cannabirone and sartix); benzodiazepines (e.g., midazolam and lorazepam); anticholinergic agents (such as scopolamine); trimethoxy benzamide; ginger; yutuning (vomiting remedy); propofol; mint; muscimol and caraway indica.
The pharmaceutical composition may be administered to the subject by any suitable route of administration. In one embodiment, the pharmaceutical composition is administered to the subject orally, parenterally, transdermally, or transmucosally. In one embodiment, the pharmaceutical composition is administered parenterally to the subject. In one embodiment, the pharmaceutical composition is administered to the subject by a parenteral route of administration selected from Intravenous (IV), Subcutaneous (SC), and Intramuscular (IM). In one embodiment, the pharmaceutical composition is administered to the subject by a route of administration selected from rectal and transdermal. In one embodiment, the pharmaceutical composition is administered to the subject in a dosage form selected from the group consisting of: sterile solutions, suspensions, suppositories, tablets and capsules. In one embodiment, the pharmaceutical composition is administered to the subject in an oral dosage form selected from the group consisting of: tablets, caplets, capsules, troches, syrups, liquids, suspensions, and elixirs. In one embodiment, the pharmaceutical composition is administered to the subject in an oral dosage form selected from the group consisting of: tablets, hard shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids, and semisolids.
In one embodiment, the pharmaceutical composition is administered to the subject in a dosage form selected from the group consisting of: sustained release, controlled release, delayed release and responsive release types.
In one embodiment, the pharmaceutical composition is administered to the subject once daily. In one embodiment, the pharmaceutical composition is administered to the subject according to an infrequent dosing schedule (e.g., once per week or less frequently). In one embodiment, the pharmaceutical composition is administered to the subject according to a frequent dosing regimen (e.g., more than once per week). In one embodiment, the pharmaceutical composition is administered to the subject once per week. In one embodiment, the pharmaceutical composition is administered to the subject once every four weeks. In one embodiment, the pharmaceutical composition is administered to the subject twice weekly. In one embodiment, the pharmaceutical composition is administered to the subject every two weeks. In one embodiment, the pharmaceutical composition is administered to the subject once every three weeks. In one embodiment, the pharmaceutical composition is administered to the subject in a repeating cycle of once a week, once every two weeks, once every three weeks, once every four weeks, or a combination thereof.
In one embodiment, the method of treatment comprises administering to a subject in need of such treatment: (i) a first therapeutic agent comprising a compound comprising an emiperidone (such as ONC201) or an analog thereof or a pharmaceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent, wherein the first and second therapeutic agents are administered simultaneously or sequentially; and further comprising determining expression of an Endoplasmic Reticulum (ER) pressure response gene in the biological sample. In one embodiment, the endoplasmic reticulum pressure response gene is selected from the group comprising, but not limited to, C/EBP homologous protein (CHOP), activated transcription factor 3(ATF3), and CHOP and ATF 3. In one embodiment, the endoplasmic reticulum stress response gene is selected from the group comprising, but not limited to, ATF3, activated transcription factor 4(ATF4), CHOP, IRE1, Binding Immunoglobulin (BiP), eukaryotic translation initiation factor 2A (eIF2A), X-box binding protein 1(XBP 1). The biological sample may be a tumor, peripheral blood mononuclear cells or a skin biopsy. The biological sample may be obtained before, during or after administration of the drug. In one embodiment, the method of treatment further comprises adjusting the dose of the first therapeutic agent to achieve induction of about 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, or greater than 600% of one or more ER stress genes. In one embodiment, the method of treatment further comprises adjusting the dose of the first therapeutic agent to achieve induction of about 50% to about 100%, about 100% to about 150%, about 150% to about 200%, about 200% to about 250%, about 250% to about 300%, about 300% to about 350%, about 350% to about 400%, about 400% to about 450%, about 450% to about 500%, about 500% to about 550%, about 550% to about 600%, or greater than 600% of the ER stress gene. In one embodiment, the method of treatment further comprises adjusting the dose of the first therapeutic agent to achieve induction of about 50% to about 100%, about 100% to about 200%, about 200% to about 300%, about 300% to about 400%, about 400% to about 500%, about 500% to about 600%, or greater than 600% of the ER stress gene.
In one embodiment, the method of treatment comprises administering to a subject in need of such treatment: (i) a first therapeutic agent comprising a compound comprising an imiperidone (e.g., ONC201) analog or a pharmaceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent, wherein the first and second therapeutic agents are administered simultaneously or sequentially; and further comprising determining expression of proteasome activity in the biological sample. In one embodiment, the proteasome activity can be chymotrypsin-like activity, trypsin-like activity and/or caspase-like activity. In one embodiment, the biological sample may be a tumor, peripheral blood mononuclear cells, or skin cells. The biological sample may be obtained before, during or after administration of the drug. In one embodiment, the method of treatment further comprises adjusting the dose to achieve inhibition of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of proteasome activity. In one embodiment, the method of treatment further comprises adjusting the dose to achieve inhibition of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of proteasome activity. In one embodiment, the method of treatment further comprises adjusting the dosage to achieve inhibition of about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or greater than about 90% of proteasome activity.
In one aspect, provided herein is a method of treatment comprising administering to a subject in need of such treatment a first therapeutic agent comprising an emiperidone (such as ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof (e.g., a di-or tri-salt), and a second therapeutic agent, the method comprising:
(i) administering the first therapeutic agent to the subject;
(ii) waiting after the time to administer the first therapeutic agent to the subject until a predetermined waiting time has elapsed; and/or until the adverse event is resolved or is being resolved; and
(iii) administering the second therapeutic agent to the subject, wherein the predetermined wait time is selected to achieve a delayed therapeutic effect of the first therapeutic agent without increasing the risk of possible combined toxic effects of the first and second therapeutic agents. In one embodiment, the predetermined waiting period is determined based on the clearance rate of the compound of the first therapeutic agent or a metabolite thereof. In one embodiment, the predetermined waiting period is determined by quantitative assessment of renal function and renal parameters. In one embodiment, the predetermined waiting time is determined by an assay for determining kidney function, wherein the assay is selected from the group consisting of: a serum level of a compound of the first therapeutic agent or a metabolite thereof; a rate of clearance of a compound of the first therapeutic agent or a metabolite thereof; a 24 hour urinary clearance of a compound of the first therapeutic agent or a metabolite thereof.
In one embodiment, the predetermined waiting period is substantially equal to the time required to systemically clear the compound of the first therapeutic agent, or a metabolite thereof, from the subject. In one embodiment, the predetermined waiting period is substantially equal to the time required to clear the compound of the first therapeutic agent, or a metabolite thereof, from the kidney in the subject. In one embodiment, the predetermined waiting time is substantially equal to the time required to clear the compound of the first therapeutic agent, or a metabolite thereof, from the liver in the subject. In one embodiment, the predetermined wait time is substantiallyEqual to the time required to totally eliminate the compound of the first therapeutic agent or a metabolite thereof from the subject. In one embodiment, the predetermined wait time is about 4 hours. In other embodiments, the wait time is 1 day. In one embodiment, the waiting period is C of the compound up to the first therapeutic agentmaxHave been in the past. In other embodiments, the wait time is after a majority of the adverse events are resolved or are being resolved. In one embodiment, the predetermined waiting period is about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In one embodiment, the predetermined wait time ranges from about 1-7 days, about 1-6 days, about 1-5 days, about 1-4 days, about 1-3 days, or about 1 to 2 days. In one embodiment, the wait time is up to 3 weeks. Previously considered as "treatment period".
When the order of administration is reversed, the first therapeutic agent or drug may be administered at a time C of the second therapeutic agent (i.e., the first administered drug)maxAfter having passed. In one embodiment, the first therapeutic agent may be administered after most or substantially all of the first drug has been eliminated from the body or the toxic effects of the first drug are resolved or are being resolved.
In one embodiment, the method of treatment further comprises monitoring the level of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic analysis. In some such embodiments, monitoring the level of the compound of the first therapeutic agent or a metabolite thereof in the subject using a pharmacokinetic analysis comprises constructing a pharmacokinetic profile of the compound of the first therapeutic agent or a metabolite thereof in the subject using concentrations of the compound of the first therapeutic agent or a metabolite thereof in at least two samples obtained from the subject at time points suitable for constructing the pharmacokinetic profile. In one embodiment, the method of treatment comprises monitoring the level of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic analysis, and collecting a sample from the subject at the point-of-care or point-of-use prior to performing the laboratory quantification by taking a sample on the point-of-care or point-of-use device or on a substrate suitable for storing the sample or by self-sampling. In one embodiment, each of the point of care devices or the point of use devices is capable of quantifying a compound of the first therapeutic agent or a metabolite thereof. In one embodiment, the method of treatment comprises monitoring the level of a compound of the first therapeutic agent or a metabolite thereof in the subject and collecting one or more samples from the subject at point of care or point of use by a biopsy device for analysis or for storage at the point of care or point of use device prior to performing the laboratory analysis. In one embodiment, the biopsy is performed after a time interval of 3-8 hours after administration of the first therapeutic agent to the subject. In one embodiment, the biopsy is performed after a time interval of 3-24 hours after administration of the first therapeutic agent to the subject. In one embodiment, the biopsy is performed after a time interval of 8-24 hours after administration of the first therapeutic agent to the subject. In one embodiment, the biopsy is performed after a time interval of 2 days after administration of the first therapeutic agent to the subject. In one embodiment, the biopsy is performed after a time interval of 3 days after administration of the first therapeutic agent to the subject. In one embodiment, the biopsy is performed after a time interval of 4 days after administration of the first therapeutic agent to the subject. In one embodiment, the biopsy is performed after a time interval of 1-7 days after administration of the first therapeutic agent to the subject.
In one embodiment, the pharmacokinetic profile comprises pharmacokinetic parameters suitable for guiding the administration of the first therapeutic agent to the subject being treated. In one embodiment, the first therapeutic agent is C after its administration over a treatment period of timemaxIn the range of about 1000ng/dL to about 1500 ng/dL. In one embodiment, during the treatment period, CmaxLess than 1500ng/dL and greater than 85 ng/dL. In one embodiment, the first therapeutic agent has a C after its administration to the subject over the treatment periodmaxIs in the range of about 1000ng/mL to about 1500 ng/mL. In one embodiment, during the treatment period, CmaxLess than 1500ng/mL and greater than 85 ng/mL.
In one embodiment, the first therapeutic agent is in the subject's blood (whole blood, plasma, or serum)Maximum concentration after administration ("C)max") is C in the following rangemax: about 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490ng/dL to about 1500 ng/dL; about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149ng/dL to about 150 ng/dL; or about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5ng/dL to about 15 ng/dL.
In one embodiment, the maximum concentration ("C") of the first therapeutic agent in the blood (whole blood, plasma, or serum) after its administrationmax") is C in the following rangemax: about 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490ng/mL to about 1500 ng/mL; about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149ng/mL to about 150 ng/mL; or about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5ng/mL to about 15 ng/mL.
In one embodiment, the maximum concentration of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) after its administration ("C max") is selected from about 1000, 1010, g,1020. 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490 ng/dL. In one embodiment, the C of the first therapeutic agent in the blood (whole blood, plasma, or serum) after its administrationmax(“Cmax") is selected from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng/dL. In one embodiment, said C of said first therapeutic agent after its administrationmaxSelected from about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14 or 14.5 ng/dL.
In one embodiment, said C of said first therapeutic agent after its administrationmaxSelected from about 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490 ng/mL. In one embodiment, said C of said first therapeutic agent after its administration maxSelected from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng/mL. In one embodiment, said C of said first therapeutic agent after its administrationmaxSelected from about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14 or 14.5 ng/mL.
In one embodiment of the present invention,said C of said first therapeutic agent following administration thereofmaxSelected from the group consisting of about 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 745, 755, 765, 775, 785, 795, 815, 825, 845, 855, 865, 875, 885, 895, 905, 945, 955, 965, 975, 985, 1005, 1015, 1025, 1045, 1085, 1245, 1085, 1185, 1165, 1185, 1125, 1185, 1125, 1255, 1185, 1085, 1185, 1125, 1185, 118, 1355. 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, 1495, or 1500 ng/dL. In one embodiment, said C of said first therapeutic agent after its administration maxSelected from about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 119, 116, 120, 125, 124, 121, 134, 121, 134, 121, 23, 84, 135. 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148 or 149 ng/dL. In one embodiment, said C of said first therapeutic agent after its administrationmaxSelected from about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12,12.5, 13, 13.5, 14 or 14.5 ng/dL.
In one embodiment, said C of said first therapeutic agent after its administration maxSelected from the group consisting of about 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 745, 755, 765, 775, 785, 795, 815, 825, 845, 855, 865, 875, 885, 895, 905, 945, 955, 965, 975, 985, 1005, 1015, 1025, 1045, 1085, 1245, 1085, 1185, 1165, 1185, 1125, 1185, 1125, 1255, 1185, 1085, 1185, 1125, 1185, 118, 1355. 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, 1495, or 1500 ng/mL. In one embodiment, said C of said first therapeutic agent after its administrationmaxSelected from about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 119, 116, 120, 125, 124, 121, 134, 121, 134, 121, 23, 84, 135. 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng/mL. In one embodiment, said C of said first therapeutic agent after its administration maxSelected from about 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng/mL.
In one embodiment, C of the first therapeutic agent after its administration to the subjectmaxRanges from about 85ng/dL to about 1500 ng/dL; about 8.5ng/dL to about 150 ng/dL; or about 0.85ng/dL to about 15 ng/dL. In one embodiment, the C of the first therapeutic agent in the blood (whole blood, plasma, or serum) after its administrationmaxSelected from the group consisting of about 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 745, 755, 765, 775, 785, 795, 815, 825, 845, 855, 865, 875, 885, 895, 905, 945, 955, 965, 975, 985, 1005, 1015, 1025, 1045, 1085, 1245, 1085, 1185, 1165, 1185, 1125, 1185, 1125, 1255, 1185, 1085, 1185, 1125, 1185, 118, 1355. 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, or 1495ng/dL to about 1500 ng/dL; about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 119, 120, 117, 125, 124, 121, 124, 129, 126, 129, 132, 121, 124, 129, 126, 121, 132, 124, 126, 129, 132, 23, 133. 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149ng/dL to about 150 ng/dL; or about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5ng/dL to about 15 ng/dL.
In one embodiment, C of the first therapeutic agent after its administrationmaxRanges from about 85ng/mL to about 1500 ng/mL; about 8.5ng/mL to about 150 ng/mL; or from about 0.85ng/mL to about 15 ng/mL. In one embodiment, C of the first therapeutic agent after its administrationmaxSelected from the group consisting of about 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 745, 755, 765, 775, 785, 795, 815, 825, 845, 855, 865, 875, 885, 895, 905, 945, 955, 965, 975, 985, 1005, 1015, 1025, 1045, 1085, 1245, 1085, 1185, 1165, 1185, 1125, 1185, 1125, 1255, 1185, 1085, 1185, 1125, 1185, 118, 1355. 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, or 1495ng/mL to about 1500 ng/mL; about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 36, 37, 60, 38, 60, 39, 40, 47, 43, 65 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149ng/mL to about 150 ng/mL; or about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5ng/mL to about 15 ng/mL.
In one embodiment, the total drug exposure as a function of time, measured as the area under the curve ("AUC") of a plot of drug concentration in the subject's blood (whole blood, plasma, or serum) after drug administration versus time after drug administration, ranges from about 150ng hr/mL to about 8000ng hr/mL; about 15ng hr/mL to about 800ng hr/mL; about 1.5ng hr/mL to about 80ng hr/mL. In one embodiment, the AUC is less than 8000ng hr/mL and greater than or equal to 150ng hr/mL. In one embodiment, the AUC is less than 800ng hr/mL and greater than or equal to 15ng hr/mL. In one embodiment, the AUC is less than 80ng hr/mL and greater than or equal to 1.5ng hr/mL.
In one embodiment, the total drug exposure over time is the AUC of: about 100ng hr/mL to about 8000ng hr/mL; about 10ng hr/mL to about 800ng hr/mL; or about 1ng hr/mL to about 80ng hr/mL. In one embodiment, the total drug exposure over time is the AUC of: about 150, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800, 5000, 5200, 5400, 5600, 5800, 6000, 6200, 6400, 6600, 6800, 7000, 7200, 7400, 7600, or 7800ng hr/mL to about 8000ng hr/mL. In one embodiment, the total drug exposure over time is the AUC of: about 15, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, or 780ng hr/mL to about 800ng hr/mL. In one embodiment, the total drug exposure over time is the AUC of: about 1.5, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, or 78ng hr/mL to about 80ng hr/mL.
In one embodiment, the total drug exposure over time is the AUC of: about 100ng hr/mL to about 8000ng hr/mL, about 10ng hr/mL to about 800ng hr/mL; or about 1ng hr/mL to about 80ng hr/mL. In one embodiment, the total drug exposure over time is the AUC of: about 150ng hr/mL to about 7800, 7600, 7400, 7200, 7000, 6800, 6600, 6400, 6200, 6000, 5800, 5600, 5400, 5200, 5000, 4800, 4600, 4400, 4200, 4000, 3800, 3600, 3400, 3200, 3000, 2800, 2600, 2400, 2200, 2000, 1800, 1600, 1400, 1200, 1000, 800, 600, 400, or 200ng hr/mL. In one embodiment, the total drug exposure over time is the AUC of: about 15ng hr/mL to about 780, 760, 740, 720, 700, 680, 660, 640, 620, 600, 580, 560, 540, 520, 500, 480, 460, 440, 420, 400, 380, 360, 340, 320, 300, 280, 260, 240, 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, or 20ng hr/mL. In one embodiment, the total drug exposure over time is the AUC of: about 1.5ng hr/mL to about 78, 76, 74, 72, 70, 68, 66, 64, 62, 60, 58, 56, 54, 52, 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 4, or 2 nghr/mL. In one embodiment, the total drug exposure over time is the AUC of: about 100ng hr/mL to about 200ng hr/mL; about 10ng hr/mL to about 20ng hr/mL; or about 1ng hr/mL to about 2ng hr/mL.
In one embodiment, the total drug exposure over time is an AUC selected from the group consisting of: about 100, 150, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 46000, 4800, 5000, 5200, 5400, 5600, 5800, 6000, 6200, 6400, 6600, 6800, 7000, 7200, 7400, 7600, 7800, and 8000ng hr/mL. In one embodiment, the total drug exposure over time is an AUC selected from the group consisting of: about 10, 15, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 4600, 480, 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, and 800ng hr/mL. In one embodiment, the total drug exposure over time is an AUC selected from the group consisting of: about 1, 15, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 460, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, and 80ng hr/mL.
In another aspect, provided herein is a method of treatment or composition for treating a disease state, the method of treatment comprising administering to a subject in need of such treatment a combination of a first therapeutic agent and a second therapeutic agent, the method comprising:
(i) administering to the subject the first therapeutic agent comprising an emiperidone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof;
(ii) monitoring the level of a compound of the first therapeutic agent or a metabolite thereof in the subject using a pharmacokinetic analysis; and
(iii) administering the second therapeutic agent conditioned on the level of the first therapeutic agent in the subject. In one embodiment, the monitoring step comprises constructing a pharmacokinetic profile of the compound of the first therapeutic agent or a metabolite thereof in the subject using the concentration of the compound of the first therapeutic agent or a metabolite thereof in a plurality of samples obtained from the subject at time points suitable for constructing the pharmacokinetic profile. At least two samples are collected at the point-of-care or point-of-use by sampling or self-sampling on the point-of-care or point-of-use device or on a substrate suitable for storing the samples prior to laboratory quantification of the compound or metabolite thereof. In one embodiment, each point-of-care device or point-of-use device is capable of quantifying a compound or a metabolite thereof. At one end In one embodiment, the pharmacokinetic profile comprises pharmacokinetic parameters suitable for guidance in administering the compound or salt thereof to the subject. In one embodiment, the sample comprises 2-12 samples. In one embodiment, the samples are collected over a period of up to 8 hours, up to 24 hours, up to 48 hours, or up to 72 hours. In one embodiment, the pharmacokinetic parameters comprise at least one parameter selected from the group consisting of: AUC, AUCinf、Tmax、CmaxTime to threshold, steady state concentration, absorbance, clearance, distribution rate, terminal T-1/2, or a parameter derived from a non-compartmental Pharmacokinetic (PK) or compartmental PK analysis (including a physiological model based compartmental PK analysis). In one embodiment, the method of treatment further comprises generating a report comprising the pharmacokinetic profile of the subject. In one embodiment, the report comprises a recommendation for dosing based on the pharmacokinetic profile of the subject. In one embodiment, lowering the dose of ONC201, an analog thereof, or a pharmaceutically acceptable salt thereof is indicated to reduce toxicity risk based on one or more pharmacokinetic parameters. In one embodiment, the AUC, or time to threshold is based on the time to threshold exceeded (where the threshold is the concentration of drug above which toxicity occurs) infOne or more of, or a combination of a set of pharmacokinetic variables in, Mean Residence Time (MRT), an index defining the pharmacokinetic profile, steady state volume of distribution (Vss), volume of distribution during terminal phase (Vz) indicating that the dose of the compound or salt thereof is reduced to adequately describe the pharmacokinetic profile. In one embodiment, adjusting the dose of the compound or salt thereof to increase efficacy is indicated based on one or more pharmacokinetic parameters. In one embodiment, based on AUC, AUCinfMRT, index defining the pharmacokinetic profile, steady state volume of distribution (Vss), volume of distribution during the terminal phase (Vz) amount, or a combination of a set of pharmacokinetic variables to indicate an increase in the dose of the compound or salt thereof to adequately describe the pharmacokinetic profile. In one embodiment, the dosage of the compound or salt thereof is adjusted to within 5% to 25% of the desired target value. In one embodiment, each of the samples is applied toA point-of-care device or a point-of-use device to determine the concentration of a compound or metabolite thereof, wherein the point-of-care device or point-of-use device comprises a lateral flow strip having a configuration and a composition such that application of one or more samples of a sample to the lateral flow strip causes a portion of a drug in the sample to bind to a component of the lateral flow strip such that a detectable signal proportional to the concentration of the drug in the applied sample is generated. In one embodiment, the sample is applied to a substrate suitable for storage of the sample prior to performing the laboratory quantification. In one embodiment, the sample is stored as a dried blood spot. In one embodiment, drug concentration is measured by ELISA, LC MS, LCUV or LCMS. In one embodiment, the pharmacokinetic parameters include steady state concentration, absorption rate, and terminal T 1/2At least one of (a). In one embodiment, at least one of the samples is whole blood.
IX. multimode treatment method
In one aspect, provided herein are multimodal treatment methods wherein the subjects in need thereof are supplemented with administration of emiperidone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof by other treatment modalities. In one embodiment, the multimodal treatment includes administering to the subject a pharmaceutical composition including emiperidone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof, in conjunction with radiation therapy or after radiation nullification has been determined. In one embodiment, the multimodal treatment comprises administering to the subject a pharmaceutical composition comprising emiperidone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof in combination with radiation therapy, wherein the pharmaceutical composition comprising emiperidone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof and the radiation therapy are administered simultaneously or sequentially in any order. In one embodiment, the multimodal treatment comprises administering in combination, in a sequential arrangement, a pharmaceutical composition comprising emiliene (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof, and radiation therapy. In one embodiment, multimodal treatment includes simultaneous administration of a pharmaceutical composition including an emiperidone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof and radiation therapy. In one embodiment, multimodal treatment is used to treat cancer. In one embodiment, the multimodal treatment comprises administering to a cancer subject a pharmaceutical composition comprising emilienone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof and irradiating the cancer cells with a radiation beam. In one embodiment, the multimodal treatment uses Conformal Radiation Therapy (CRT) to deliver prescribed Dose Volume Histograms (DVHs) to cancer subjects. In one embodiment, the multimodal treatment method uses Intensity Modulated Radiation Therapy (IMRT) to deliver radiation to cancer cells. In one embodiment, the multimodal treatment method uses a technique to compensate for tumor motion in the subject during treatment (e.g., where a radiation dose must be administered to a breast tumor that moves as the patient breathes). For example, multi-modal therapy uses a four-dimensional computed tomography (4DCT) scanning technique to adjust the delivered radiation field to compensate for tumor motion throughout the respiratory cycle.
Any suitable type of radiation (including fractionated gamma radiation), IMRT (intensity modulated radiation therapy), gamma knife, proton therapy, and brachytherapy can be used for the multi-modality treatment. Radiotherapy and administration of emilienone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof can be used to treat a brain tumor, e.g., glioblastoma or a disease that has metastasized to the brain from lung cancer. The multimodal treatment can be used for treating lung cancer, pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostate cancer, gynecological malignancies and lymphomas. Gamma knives are frequently used to treat brain metastases. In one embodiment, multimodal therapy comprises the use of proton therapy to treat cancer, including brain tumors, prostate cancer, and any tumor adjacent to vital organs, where it is important to minimize toxicity to nearby normal tissues.
In one embodiment, multimodal treatment comprises administering to a cancer subject, simultaneously or in combination, a pharmaceutical composition comprising an imidazolone (such as ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof, in combination with an adoptive cell therapy (e.g., CAR-T (
In one embodiment, the multimodal treatment eliminates minimal residual disease without increasing toxicity resulting from treatment with emilienone (e.g., ONC201), an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, multimodal treatment improves prognosis and/or reduces adverse side effects associated with a disease state or condition in a subject undergoing treatment.
Additional derivatives, analogs and salts of isometridone
In one aspect, provided herein are analogs of compounds of formula (10) and methods for their preparation. It will be understood by those skilled in the art that the general principles and concepts described herein (including those related to methods and pharmaceutical compositions) in connection with ONC201 and compounds of formula (10) and salts thereof apply in an equivalent manner to the following analogs and salts thereof.
In one embodiment, the analog has the structure of compound (25):
wherein Y is NR4Or O, and wherein R1、R2、R3And R4Independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, carboxy, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclyl. In one embodiment, R 1、R2、R3And R4Is optionally substituted. In one embodiment, R1、R2、R3And R4Some or all of the hydrogens in the group are replaced with deuterium. In other embodiments, R1、R2、R3And R4Independently selected from the group consisting of: H. c1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazines and C1-4Alkylthienyl, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones and C1-4Benzyl-piperazine optionally substituted by C1-4Alkyl, hydroxy or halo substituted. In still other embodiments, R1、R2、R3And R4Independently selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph。
In one embodiment, the analog has the structure of compound (26):
wherein R is1And R2Independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, carboxy, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclyl. In one embodiment, R 1And R2Independently selected from the group consisting of: H. c1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazines and C1-4Alkylthienyl, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones and C1-4Benzyl-piperazine optionally substituted by C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, R1Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-P)h)、CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph. In one embodiment, R2Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph。
In one embodiment, R1Is benzyl optionally substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen, comprising F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl. In one embodiment, R2Is benzyl substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH 3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen.
In one embodiment, R1Is H. In one embodiment, R1Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution.
In one embodiment of the present invention,R2is a substituted or unsubstituted arylalkyl group, such as benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the arylalkyl group is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3. In one embodiment, R2Is a substituted or unsubstituted heterocycloalkylalkyl group, such as morpholinylalkyl or piperazinylalkyl. In one embodiment, R2Is a substituted or unsubstituted heteroarylalkyl group, such as isoxazolidinylmethyl or pyridylmethyl. In one embodiment, the heterocycloalkyl or heteroarylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of: halo, -CH 3、-CF3and-OCH3。
In one embodiment, the analog has the structure of compound (27):
wherein R is1Is H, alkyl, cycloalkyl, cycloalkylalkyl, carboxy, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclyl. In one embodiment, R1Selected from the group consisting of: H. c1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazines and C1-4Alkylthienyl, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkyl radicalPhenyl ketones and C1-4Benzyl-piperazine optionally substituted by C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, R1Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph。
In one embodiment, R1Is benzyl optionally substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH 3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen, comprising F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl. In one embodiment, R1Is H. In one embodiment, R1Is a substituted or unsubstituted arylalkyl group, such as benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution.
In one embodiment, the analog has the structure of compound (28):wherein R is1And R2Independently represents H, alkyl, cycloalkyl, cycloalkylalkyl, carboxy, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkyloxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinylArylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclyl. In one embodiment, R1And R2Independently selected from the group consisting of: H. c1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazines and C1-4Alkylthienyl, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C 1-4Alkylphenyl ketones and C1-4Benzyl-piperazine optionally substituted by C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, R1Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh、CH2CH2(4-N-benzyl-piperazine) and (CH)2)3CO-4F-Ph. In one embodiment, R2Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph. In one embodiment, when R1Is CH2At Ph, R2Is not CH2-(2-CH3-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2-(2-CH3-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2- (2, 4-di F-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2-(4-CF3-Ph)。
In one embodiment, R1Is benzyl optionally substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen, comprising F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl. In one embodiment, R2Is benzyl substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH 3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen.
In one embodiment, R1Is H. In one embodiment, R1Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution.
In one embodiment, R2Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the arylalkyl group is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3. In one embodiment, R2Is a substituted or unsubstituted heterocycloalkylalkyl group, for example, morpholinylalkyl or piperazinylalkyl. In one embodiment, R2Is a substituted or unsubstituted heteroarylalkyl group, such as isoxazolidinylmethyl or pyridylmethyl. In one embodiment of the present invention,heterocycloalkylalkyl or heteroarylalkyl with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C 1-4Alkyl or halo substitution. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3。
In one embodiment, the analog has the structure of compound (29):
wherein R is1And R2Independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, carboxy, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclyl. In one embodiment, R1And R2Independently selected from the group consisting of: H. c1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazines and C1-4Alkylthienyl, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones and C1-4Benzyl-piperazine optionally substituted by C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, R1Selected from the group consisting of: H. CH (CH) 3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph. In one embodiment, R2Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph. In one embodiment, when R1Is CH2At Ph, R2Is not CH2-(2-CH3-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2-(2-CH3-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2- (2, 4-di F-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2-(4-CF3-Ph)。
In one embodiment, R1Is benzyl optionally substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is a halogen comprising: refers to F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl. In one embodiment, R2Is benzyl substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen.
In one embodiment, R 1Is H. In one embodiment, R1Is substituted or notSubstituted arylalkyl groups, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution.
In one embodiment, R2Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the arylalkyl group is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3. In one embodiment, R2Is a substituted or unsubstituted heterocycloalkylalkyl group, for example, morpholinylalkyl or piperazinylalkyl. In one embodiment, R2Is a substituted or unsubstituted heteroarylalkyl group, such as isoxazolidinylmethyl or pyridylmethyl. In one embodiment, the heterocycloalkyl or heteroarylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of: halo, -CH 3、-CF3and-OCH3。
In one embodiment, the analog has the structure of compound (30):
wherein R is1And R2Independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, carboxy, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl and heterocyclyl. In one embodiment, R1And R2Independently selected from the group consisting of: H. c1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazines and C1-4Alkylthienyl, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones and C1-4Benzyl-piperazine optionally substituted by C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, R1Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph. In one embodiment, R2Selected from the group consisting of: H. CH (CH)3、CH2Ph、CH2-((2-Cl)-Ph)、CH2- (2-thienyl), CH 2CH2Ph、CH2CH2(4-N-benzyl-piperazine), CH2- (2, 4-di F-Ph), CH2-((2-CH3)-Ph)、CH2CHOHPh and (CH)2)3CO-4F-Ph. In one embodiment, when R1Is CH2At Ph, R2Is not CH2-(2-CH3-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2-(2-CH3-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2- (2, 4-di F-Ph). In one embodiment, R1Is CH2Ph and R2Is CH2-(4-CF3-Ph)。
In one embodiment, R1Is benzyl optionally substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is a halogen comprising: refers to F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl. In one embodiment, R2Is benzyl substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen.
In one embodiment, R1Is H. In one embodiment, R1Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C1-4Alkyl radical, C 1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution.
In one embodiment, R2Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, arylalkyl is halogenated, hydroxy, C1-4Alkyl radical, C1-4Alkoxy or perhalogenated C1-4Alkyl substitution. In one embodiment, the arylalkyl group is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3. In one embodiment, R2Is a substituted or unsubstituted heterocycloalkylalkyl group, for example, morpholinylalkyl or piperazinylalkyl. In one embodiment, R2Is a substituted or unsubstituted heteroarylalkyl group, for example, isoxazolidinylmethyl or pyridylmethyl. In one embodiment, the heterocycloalkyl or heteroarylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3。
In one embodiment, the analog has the structure of compound (31):
In one embodiment, R1Is benzyl optionally substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen, comprising F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl. In one embodiment, R2Is benzyl substituted with one or more of the following substituents, alone or in combination, at the ortho, meta and/or para positions of the benzyl ring: -CH3、-NO2、-OCH3、-CXH2、-CX2H、-CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3or-OCpX2p+1Wherein p is an integer from 2 to 20 and wherein X is halogen.
In one embodiment, R1Is H. In one embodiment, R1Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the aromatic hydrocarbonRadical alkyl quilt C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution.
In one embodiment, R2Is a substituted or unsubstituted arylalkyl group, for example, benzyl or phenethyl. In one embodiment, the arylalkyl group is substituted with C 1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the arylalkyl group is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3. In one embodiment, R2Is a substituted or unsubstituted heterocycloalkylalkyl group, for example, morpholinylalkyl or piperazinylalkyl. In one embodiment, R2Is a substituted or unsubstituted heteroarylalkyl group, for example, isoxazolidinylmethyl or pyridylmethyl. In one embodiment, the heterocycloalkyl or heteroarylalkyl group is substituted with C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of: halo, -CH3、-CF3and-OCH3。
In one embodiment, provided herein is a compound of formula (100):wherein R is1And R2Independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, and acyl. In one embodiment, R 1Is CH2Ph and R2Is CH2-(2-CH3Ph) is the ONC201 linear isomerIts lack of resistanceCancer activity (Jacob et al, applied chemistry in Germany, (Angew. chem. int. Ed.), (2014)53: 6628; Wagner et al, tumor target (Oncotarget.), (2015)5(24) 12728). TIC-10 is a CXCR7 agonist. CXCR7 agonists may be used for liver regeneration and to prevent or treat liver fibrosis.
In one embodiment, R1And R2Independently selected from the group consisting of: H. c1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazine, C1-4Alkylthienyl, C1-4Alkyl pyridyl radical, C1-4Alkyl isoxazolidinyl, C1-4Alkyl morpholinyl, C1-4Alkylthiazolyl and C1-4Alkyl pyrazinyl radical, wherein C1-4Alkyl radical, C1-4Alkyl phenyl, C1-4Alkylphenyl ketones, C1-4Benzyl-piperazine, C1-4Alkylthienyl, C1-4Alkyl pyridyl radical, C1-4Alkyl isoxazolidinyl, C1-4Alkyl morpholinyl, C1-4Alkylthiazolyl and C1-4Alkyl pyrazinyl optionally substituted by C1-4Alkyl radical, C1-4Alkoxy, hydroxy, perhalogenated C1-4Alkyl or halo substitution. In one embodiment, R1And/or R2Is a substituted or unsubstituted arylalkyl or heteroarylalkyl group. In one embodiment, heteroarylalkyl is selected from C1-4Alkyl pyrrolyl, C1-4Alkyl furyl group, C 1-4Alkyl pyridyl radical, C1-4Alkyl-1, 2, 4-thiadiazolyl, C1-4Alkyl pyrimidinyl radical, C1-4Alkylthienyl, C1-4Alkyl isothiazolyl, C1-4Alkylimidazolyl group, C1-4Alkyl tetrazolyl, C1-4Alkyl pyrazinyl, C1-4Alkyl pyrimidinyl radical, C1-4Alkyl quinolyl, C1-4Alkyl isoquinolinyl, C1-4Alkylthiophenyl radical, C1-4Alkylbenzothienyl, C1-4Alkyl isobenzofuranyl, C1-4Alkyl pyrazolyl, C1-4Alkyl indolyl radical, C1-4Alkyl purine radical, C1-4Alkyl carbazolyl group, C1-4Alkylbenzimidazolyl and C1-4An alkyl isoxazolyl group.
In one embodiment, R1And/or R2Is benzyl optionally substituted with one or more of the following substituents on the benzyl ring: x, -CH3、-NO2、-OCH3、-CN、-CXH2、-CX2H、C2-C4Alkyl, -CX3、-CH2(CX3)、-CH(CX3)2、-C(CX3)3、-CpX2p+1、-OCX3、-OCpH2p+1、-OCpX2p+1、ORm、SRm、NRmRn、NRmC(O)Rn、SORm、SO2Rm、C(O)RmAnd C (O) ORm；RmAnd RnIndependently selected from H or C1-C4An alkyl group; and wherein p is an integer from 2 to 20 and X is halogen, comprising F, Cl, Br or I; preferably, F, Cl or Br; more preferably, F or Cl.
XI example
It should be understood that the following description and examples are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. The following examples are intended to illustrate the disclosed embodiments and should not be construed as limiting the embodiments. In addition to those compounds described below, additional compounds may be prepared by the following reaction schemes or appropriate variations or modifications thereof.
EXAMPLE 1 Synthesis of 2-chlorobenzylamino-2-imidazolidine hydroiodide
To a stirred solution of 2-methylsulfanyl-2-imidazolidine hydroiodide (244mg, 1.00mMol) in dry dioxane (2.0mL) was added 2-chlorobenzylamine (141mg, 1.0 mMol). The reaction mixture was stirred under argon at 70 ℃ for 90 minutes. The solution was cooled to room temperature, filtered on a sintered funnel, washed with cold dioxane (2mL) and dried under vacuum. The white
EXAMPLE 2 Synthesis of 2-chlorobenzylamino-2-imidazoline
To a stirred solution of 2-chlorobenzylamino-2-imidazolidine hydroiodide (242mg, 0.72mMol) in water (3mL) at 7 deg.C was added 1.0N sodium hydroxide (2 mL). The reaction mixture was stirred under argon at 7 ℃ for 30 minutes. Dichloromethane (5mL) was then added and the mixture was stirred for an additional 5 minutes. The reaction mixture was extracted with dichloromethane (2X 2.5 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and evaporated. The resulting free base (150mg, 100%) was a viscous liquid and was used in the next reaction without further purification. MS (ESI)210(M + H).
EXAMPLE 3 Synthesis of methyl-1-benzyl 4-oxo-3-piperidinecarboxylic acid ester (Compound (6)).
To a stirred solution of methyl-1-benzyl 4-oxo-3-piperidinecarboxylic acid ester hydrochloride (5.7g, 20mMol) in ethyl acetate (50mL) was added triethylamine (6mL) at 7 ℃. The reaction mixture was stirred at 7 ℃ for 30 minutes under argon atmosphere. The reaction mixture was extracted with ethyl acetate (2X 50mL) and washed with water (50 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and evaporated. The resulting free base residue (5, R)1Pivaloyl) was a viscous oil that was used for the next reaction without any further purification, ms (esi)248(M + H)
Example 4 Synthesis of ONC202 (Compound (14))
To a solution of 2-chlorobenzylamino-2-imidazoline (150mg, 0.72mMol), 1-benzyl 4-oxo-3-piperidinecarboxylate (5, R)1Benzyl) (195mg, 0.79mMol) in 1-butanol (2mL) was added PPTS (10mg) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then refluxed at 125 ℃ to 130 ℃ for 2 hours. The solvent was removed in vacuo, extracted with ethyl acetate (10mL), and washed with saturated sodium bicarbonate solution (2 × 10mL) and water (10 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and evaporated. The crude free base was purified by RP HPLC (10% -40% acetonitrile/water) to give ONC202 TFA salt as a white solid (228mg, 50% yield), ms (esi)407(M + H).
The same procedure is used to prepare various analogues, e.g.,
Example 5 Synthesis of ONC207 (Compound (19))
To a suspension of 60% sodium hydride (3.5g, 88mMol) in dry toluene (50mL) was added dimethyl carbonate (4.32g, 48.0mMol) dropwise under nitrogen at room temperature for 0.5 h. After addition of a few drops of methanol, 1-tert-butoxycarbonyl-4-piperidone (4.8g, 24mMol) dissolved in dry toluene (20mL) was added dropwise to the reaction mixture while stirring at 80 ℃ for 1 hour. The reaction mixture was stirred at the same temperature for 3 hours and then cooled to 0 ℃ (ice bath) and adjusted to pH 6-6.5 with acetic acid. The resulting cold mixture was diluted with water (10mL) and the pH adjusted to 8 with 5% sodium hydroxide solution. The toluene layer was separated and the aqueous layer was extracted with toluene (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The compound was dried under vacuum to give methyl-1-tert-butoxycarbonyl-4-oxo-3-piperidinecarboxylic acid ester (5.0g, 80%). The resulting compound was used for the next reaction without further purification.
To 1-butanol (2mL) containing 2-methylbenzylamino-2-imidazoline (190mg, 1mMol), 1-tert-butoxycarbonyl-4-oxo-3-piperidinecarboxylate (315mg, 1.1mMol) was added PPTS (10.0mg) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then refluxed at 125 ℃ to 130 ℃ for 2 hours. The solvent was removed in vacuo, extracted with ethyl acetate (10mL), washed with saturated sodium bicarbonate solution (2X 10mL) and water (10 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and evaporated. The crude free base was cleaved with 10% trifluoroacetic acid in dichloromethane and purified by RP HPLC (10% -40% acetonitrile/water) to give ONC207(262mg, 50%) TFA salt as a white solid, ms (esi)297(M + H).
Example 6 Synthesis of ONC209 (Compound (21))
A mixture of N, N-dimethylformamide (3mL) containing ONC207(100mg, 0.2mMol), phenethylbromide (55.0mg, 0.28mMol) and potassium carbonate (150mg, 1.0mMol) was heated to 70 deg.C for 12 hours. The solvent is removed under vacuumExtracted with ethyl acetate (10mL) and washed with water (5 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and evaporated. The crude free base was purified by RP HPLC (10% -40% acetonitrile/water) to give ONC209(62mg, 50%) TFA salt as a white solid, ms (esi)401(M + H).
The same procedure was used starting from different halides to give ONCs 215 and 214. Compounds 227, 228, 229, 230, 231, 232, 233, 234, 235 and 236 were prepared using a similar procedure as in examples 1 and 5 starting from different benzylamines. Then treating with a different halide as above wherein R1An intermediate compound which is H.
Compound ONC216 was prepared by treating ONC215 with TFA.
Compound (72) was prepared by reacting a precursor NH compound prepared similarly to example 5 and treating it with styrene oxide.
Example 7 Synthesis of ONC208 (Compound (20))
To a solution of 2-methylbenzylamino-2-imidazoline (190.0mg, 1.0mMol), 1-methyl 4-oxo-3-piperidinecarboxylate (185.0mg, 1.0mMol) in 1-butanol (2.0mL) was added PPTS (10.0mg) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then refluxed at 125 ℃ to 130 ℃ for 2 hours. The solvent was removed in vacuo, extracted with ethyl acetate (10mL), washed with saturated sodium bicarbonate solution (2X 10mL) and water (10 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and evaporated. The crude free base was purified by
Example 8 Synthesis of ONC201 (Compound (1))
Into a 2L round bottom flask, 800mL of saturated NaHCO with stirring3Compound (3) (239.7g, 0.845mol, 1.6 equiv) was added in portions. N-butanol (500mL) was added to the resulting mixture, which was stirred for 30 minutes and then transferred to a separatory funnel. The organic phase containing compound (4) is separated and transferred to a device equipped with mechanical stirring, N2Inlet, thermocouple, condenser and dean-starkWater trap (Dean-Stark trap) in a 2L three-neck round bottom flask. To the contents of the flask was added compound (5) (100g, 0.528mol, 1 eq.) and pyridinium p-toluenesulfonate (PPTS) (6.63g, 0.026mol, 5 mol%). The resulting mixture was heated to reflux for 6 hours. The water in the reaction mixture was separated into a dean-stark trap as needed. The reflux temperature increased from 93 ℃ to 118 ℃. The progress of the reaction was monitored by HPLC. The reaction was stopped when the peak area of compound (1) on HPLC remained constant with reaction time.
Example 9 Synthesis of a disalt of ONC201 (Compound (1)2HCl)
The reaction mixture from example 8 was washed with water (500mL) and diluted with methyl tert-butyl ether (MTBE) (800mL) without isolation of compound (1). The organic phase was washed with water (500 mL. times.2) and transferred to a column equipped with mechanical stirring, N 2Inlet, thermocouple, condenser and dean-stark trap in a 3L three-necked round bottom flask. While stirring the reaction mixture, a 1N HCl in dioxane-MTBE solution (4N HCl in dioxane: 300mL, 1.2mol, 2.27 equivalents; MTBE: 1200mL) was added dropwise until no more solid precipitated out of the reaction mixture after HCl addition. The reaction mixture was heated to reflux at 60-65 ℃ for 2 hours. The water was separated into a dean-stark trap as needed. After cooling to room temperature, the solid precipitate was filtered through a sintered glass funnel and washed with n-butanol-MTBE (1:2, 600mL) and MTBE (600mL), respectively. The solid was dried overnight (16 hours) in a vacuum oven at 65 ℃ to give 200g of a yellow solid.
Equipped with mechanical stirring, N2A2L three neck round bottom flask with inlet, thermocouple and condenser was charged with the above solid (200g) followed by ethanol (1000 mL). The mixture was heated to reflux at 78 ℃ for 2 hours. After cooling to room temperature, the solid was filtered through a sintered glass funnel and washed with ethanol (200mL × 3). The wet solid was dried in a vacuum oven at 85 ℃ for 3 days until the residual solvent met the specifications. 120g of compound (2) are obtained in 49% yield as a white solid with an HPLC purity of 99.7%.
EXAMPLE 10 Activity of Imipritone
Many isometriones were prepared based on the above syntheses. Viability of human cancer cells was measured 72 hours after treatment with each compound. The potency change (relative to ONC201) was determined and shown in table 3.
Table 3: relative potency of ONC201 analogs
Potency relative to ONC 201; a indicates > 2-fold increase in potency of ONC 201; b indicates 2-fold efficacy within ONC 201; and C indicates > 2-fold reduction in potency of ONC 201.
ONC212
Determination of IC of ONC201 and ONC212(5 nM-5. mu.M, 72 hours) following treatment with several Acute Myeloid Leukemia (AML) cell lines (n ═ 3)50And is shown in table 4.
TABLE 4
AML cell line
ONC201 IC50(μM)
ONC212 IC50(μM)
MV411
3.25
0.01
HL60
>5
0.21
MOLM14
3.92
0.01
Cell viability of MV411AML cells treated with ONC212 and cytarabine (5nM-5 μ M, 24 hours) (n ═ 3) was measured (fig. 10A). In addition, cell viability was measured for MOLM14, MV411AML cells, MRC5 lung fibroblasts, and Hs27a bone marrow cells treated with ONC212(5nM-5 μ M, 72 hours) (n ═ 3) (fig. 10B). Cell viability was measured for MOLM14 and MV411AML cells treated with ONC212(250nM) for 4, 8, 24, 48, 72 and 96 hours. ONC212 medium was replaced with fresh medium at these time points and cell viability was determined for all samples at 96 hours. (n-2) (fig. 10C).
In addition, a single ONC212 dose administered orally or intraperitoneally to mice carrying human colon cancer xenografts resulted in a significant reduction in tumor volume compared to vehicle treated control groups. ONC212 has a wide therapeutic window because the dosage of ONC212 in mice is well tolerated at least up to 225 mg/kg.
In addition, ONC212 demonstrated efficacy in an AML xenograft model against ONC201 (fig. 11). MV411 AML cells (5X 10)6) Subcutaneously implanted in the flank of athymic nude mice. ONC212 and ONC201 were administered orally (PO) as indicated. Tumor volumes (a and B) and body weights (C) were measured on the indicated days (n ═ 10). Denotes relative to the vector p<0.05。
The efficacy of ONC212 in AML was assessed in vitro and the efficacy of ONC212 was 400-fold higher than that of ONC201 (table 4). ONC212 was also effective in AML cells against cytarabine standard of care (fig. 10A). Despite robust improvement in efficacy, ONC212 maintained a broad therapeutic window in vitro and was not toxic to normal cells at effective concentrations (fig. 10B). An 8 hour exposure of 250nM ONC212 was sufficient to cause a robust reduction in cell viability in MOLM14 and MV411 AML cells (fig. 10C). The ONC201 requires at least 24-48 hours of exposure to achieve efficacy.
ONC212 efficacy was determined in a leukemia xenograft model of MV411 AML cells with cytarabine resistance standard of care (figure 11). Once weekly oral administration of ONC 21250 mg/kg significantly reduced leukemic xenograft growth, while a similar dose of ONC201 was not effective in this model (fig. 11A). Interestingly, 25mg/kg once every two weeks and 5mg/kg once a week/two weeks of ONC212 was not effective (FIG. 11B). These ONC212 administration regimens were not associated with weight loss (fig. 11C) or overall observations.
ONC 21225 mg/kg represents NOAEL in a non-GLP oral single dose study in mice and rats, which is also an effective dose in a mouse xenograft study. Toxicity of ONC212 was approximately 10-fold higher than ONC201 (NOAEL 225mg/kg in rat non-GLP oral single dose study).
ONC206
ONC206 exhibited efficacy in the ewing's sarcoma xenograft model. MHH-ES-1 Ewing's sarcoma cells (5X 10)6) Subcutaneously implanted in the flank of athymic nude mice. ONC206(PO) and methotrexate (IV) were administered on
In addition, the IC of ONC201 and ONC206(5nM-5 μ M, 72 hours) after treatment with several cell lines (n ═ 3) was determined 50And is shown in table 5 below.
TABLE 5
Cell lines
ONC201 IC50(μM)
ONC206 IC50(μM)
MV411(AML)
3.25
0.2
K562(CML)
>5
0.22
MOLM14(AML)
3.92
0.27
MHH-ES-1 (Ewing's sarcoma)
5.65
0.61
HFF (Normal fibroblast)
>5
The in vitro efficacy of ONC206 showed a 20-fold improvement compared to ONC201 and no in vitro toxicity to normal cells at therapeutic doses (table 5). In the rat non-GLP oral single dose study, only a 2-fold increase in toxicity of ONC206 (NOAEL125mg/kg) over ONC201(NOAEL 225mg/kg) overall was noted. In vivo efficacy in the avirulent ewing sarcoma model (figure 12). ONC206 efficacy was comparable to methotrexate chemotherapy, but chemotherapy was associated with weight loss.
ONC213
In vitro assays of arrestin recruitment (GPCR activation marker) for GPCR activity using heterologous reporter assays indicate that ONC213 selectively targets DRD2/3 and GPR 132/91. Dual targeting of DRD2/3 and GPR132/91 represents a novel strategy for non-toxic anti-cancer efficacy. ONC213 is a DRD2/3 inhibitor and a GPR132/91 agonist. The DRD2/3 potency of ONC213 was greater than ONC201 but less than ONC 206. GPR132 potency of ONC213 was less than ONC 212. Specifically, ONC213 demonstrated similar in vitro anti-cancer efficacy in HCT116/RPMI8226 cancer cells as ONC212, but the in vitro toxicity of ONC213 to normal cells was reduced compared to ONC212 (fig. 13). The safety profile of ONC213 was demonstrated to be three times that of ONC212(25mg/kg) in a NOAEL 75mg/kg mouse MTD study. The GPR91 agonist activity of ONC213 provides opportunities for immunological, immunooncological and hematopoietic applications (Nature Immunology 9:1261(2008), journal of leukocyte biology 85 (J Leukoc Biol.) (5: 837 (2009)).
ONC237
In vitro assays of arrestin recruitment (GPCR activation marker) for GPCR activity using heterologous reporter assays indicate that ONC237 selectively targets GPR132 and
ONC236
In vitro assays of arrestin recruitment (GPCR activation marker) for GPCR activity using heterologous reporter assays indicate that ONC236 is a highly selective GPR132 agonist. Anticancer efficacy (IC) of ONC236 in HCT116 cells5088nM) was comparable to ONC212(10nM), superior to ONC206/ONC201, and superior to ONC201 but not superior to ONC212 in terms of response integrity.
ONC234
In vitro analysis of GPCR activity using a heterologous reporter assay for arrestin recruitment (GPCR activation marker) indicated that ONC234 is a broad spectrum and potent GPCR targeting small molecules. ONC234 hits several GPCRs, which comprise antagonist activity for the epinephrine, histamine, serotonin, CHRM, CCR, DRD2/5 receptor and CXCR7 agonist activity. Anticancer efficacy (IC) of ONC236 in HCT116 cells 50234nM) similar to ONC206, the response integrity was the same as ONC212 and better than ONC 201.
Example 11 GPCR antagonism of ONC201
ONC201 was evaluated in a whole-cell functional assay of β -arrestin G protein-coupled receptor (GPCR) activity that measures dopamine receptor activity directly by detecting the interaction of β -arrestin with an activated GPCR acting as a reporter. For each dopamine receptor (DRD1, DRD2S, DRD2L, DRD3, DRD4 and DRD5), cell lines overexpressing the reporter constructs were expanded from the freezer. Cells in a total volume of 20 μ L were seeded into white-walled 384-well microplates and incubated at 37 ℃ prior to testing, at EC80At concentrations, the agonist and antagonist were used sequentially. Intermediate dilutions were performed on the sample stock to generate assay buffer containing 5 x sample. 3.5 μ L of 5 × sample was added to the cells and incubated at 37 ℃ or room temperature for 30 minutes; the carrier concentration was 1%. Will contain 5. mu.L of 6 × EC80Agonist assay buffer was added to the cells and incubated at 37 ℃ or room temperature for 90 or 180 minutes prior to assay reading. The% antagonism was calculated using the following formula: antagonism of 100% × (1- (test sample mean RLU-vehicle control mean RLU)/(EC) 80Control mean RLU-vehicle control mean RLU).
Example 12: selective antagonism of DRD2 by ONC 201.
ONC201 is the first class of small molecules found in phenotypic screens for p 53-independent inducers of a tumor-selective pro-apoptotic pathway. Based on significant efficacy and superior safety against aggressive and refractory tumors, oral ONC201 was evaluated as a novel therapeutic in five early clinical trials against select advanced cancers.
In this example, prediction and validation of selective direct molecular interactions between ONC201 and specific dopamine receptor family members is reported. Experimental GPCR analysis indicated that ONC201 selectively antagonizes the D2-like but not the D1-like dopamine receptor subfamily. Reporter gene assays in heterologous expression systems showed that ONC201 selectively antagonized short and long subtypes of DRD2 and DRD3, with DRD4 being less potent and DRD1 or DRD5 being non-antagonistic. Increased prolactin secretion is a clinical marker of DRD2 antagonism caused by several psychotropic drugs that potently target this receptor. In the first human trials of advanced solid tumors, ELISA measurements of peripheral blood of patients treated with ONC201 confirmed 10/11 that the patients evaluated showed prolactin induction (2 fold on average).
Using the TCGA database, the D2-like dopamine receptor subfamily (specifically DRD2) is ubiquitous and selectively overexpressed in several malignancies. Preclinical reports show that DRD2 inhibition confers antitumor efficacy without killing normal cells through ATF4/CHOP induction and inhibition of Akt and ERK signaling, both attributes of ONC 201.
Method of producing a composite material
ONC201 dihydrochloride is available from Oncoceutics corporation. Kinase inhibition assays for the kinase panel were performed as described (see antassiadis et al, Nature Biotech 29:1039 (2011)). GPCR arrestin recruitment and cAMP regulation reporter assay were performed as described (see McGuinness et al, Journal of Biomolecular Screening 14:49 (2009)). PathHunter (Discovex) β -arrestin cells expressing one of several GPCR targets were seeded onto 384-well white solid bottom assay plates (Corning 3570) at 5000 cells per well in a volume of 20 μ L in appropriate cell plating reagents. Cells were incubated at 37 ℃ with 5% CO2The incubation was continued for 18-24 hours. In the content of 0.05% ofSamples were prepared in buffer of fatty acid BSA (Sigma). For agonist mode testing, samples (5 μ L) were added to the pre-plated cells and 5% CO at 37 ℃ 2Incubate for 90 minutes. For antagonist mode testing, samples (5 μ L) were added to the pre-plated cells and 5% CO at 37 ℃2Incubate for 30 min, then 5% CO at 37 ℃2Adding EC80Agonist (5 μ L) was continued for 90 minutes. For Hild analysis (Schild analysis), a sample (5. mu.L) was added to the pre-plated cells and 5% CO at 37 ℃2Incubate for 30 min, then 5% CO at 37 ℃2Next, serial dilutions of agonist (5. mu.L) were added for 90 minutes. Parallel tests define control wells for maximum and minimum response for each assay format. Arrestin recruitment was measured by addition of 15 μ l pathhonter assay reagent and incubated for 1-2 hours at room temperature and read on a Perkin Elmer Envision plate reader. For agonist and antagonist testing, data were normalized for percent efficacy using appropriate controls and fitted to sigmoidal dose response (variable slope), Y ═ bottom + (top-bottom)/(1 +10^ ((LogEC)50-X) slope), wherein X is the logarithmic compound concentration. For the hild analysis, the data were normalized for percent efficacy using appropriate controls and a global fit was used to fit a gardner/hild (gaddem/Schild) EC 50Displacement, where Y ═ bottom + (top-bottom)/(1 +10^ ((LogEC-X) × slope), Antag ═ 1+ (B/(10^ (-1 × pA2))) > Hilde slope and LogEC ═ Log (EC)50Antag). EC is performed in the CBIS data analysis suite (Cheminnovation)50/IC50Analyzed and hilted analysis was performed in GraphPad Prism 6.0.5.
Results
ONC201 is a small molecule in a phase II clinical trial against a select advanced stage cancer. P 53-independent inducers of the pro-apoptotic TRAIL pathway were found in phenotypic screens. Although the ONC 201-induced ATF4/CHOP up-regulation and Akt/ERK signaling inactivation (Allen et al, scientific transformed medicine 5,171ra117-171ra117(2013)) have been characterized for their contribution to their anti-cancer activity, their molecular binding targets remain elusive.
In vitro analysis of GPCR activity using a heterologous reporter assay for arrestin recruitment (a marker of GPCR activation) indicated that ONC201 selectively antagonizes the D2-like (DRD2/3/4) but not the D1-like (DRD1/5) dopamine receptor subfamily (figure 1). Antagonism of the adrenoreceptor alpha receptor or other GPCRs was not observed under the conditions evaluated. In the DRD2 family, ONC201 antagonizes both short and long subtypes of DRD2 and DRD3, with DRD4 being less potent. By means of Gard/Hilded EC 50Further characterization of the antagonism of DRD2L by ONC 201-mediated arrestin recruitment was assessed by a shift assay that determined the dissociation constant of ONC201 to be 2.9 μ M, which is equivalent to its effective dose in many human cancer cells. A confirmed result of cAMP modulation in response to ONC201 was obtained, which is another measure of DRD2L activation. The ability of dopamine to reverse dose-dependent antagonism of up to 100 μ MONC201 indicates that DRD2L has direct competitive antagonism. Consistent with the ONC201 specificity predicted by BANDIT, no significant interaction was identified between ONC201 and nuclear hormone receptors, kinase panels, or other drug targets for FDA-approved cancer therapies. Interestingly, the biologically inactive structural isomer of ONC201 (Wagner et al, tumor target 5:12728(2014)) does not inhibit DRD2L, suggesting that antagonism of this receptor may be associated with its biological activity. Taken together, these studies demonstrate that ONC201 selectively antagonizes the D2-like dopamine receptor subfamily, which appears to be a promising therapeutic target in oncology, and ONC201 is the first compound to utilize this therapeutic paradigm in several ongoing phase II clinical studies.
Example 13: preclinical data for H3K 27M adult and pediatric gliomas.
H3K 27M was found to occur as an oncogenic mutation in the context of midline gliomas involving the thalamus, pons or spinal cord. H3K 27M refers to a specific mutation in the histone H3 protein. These tumors have not been surgically operable (particularly in the brainstem where the pons are located) because of their location (the brain regions involved in critical physiological functions). This means that until recently, midline gliomas such as diffuse endogenous brain bridge glioma (DIPG) were diagnosed only on the basis of radiographic images. Recent advances in neurosurgical technology and increased parental consent for post-mortem tumor tissue extraction have resulted in the availability of adequate biological samples that enable systematic genomic assessment of DIPG and other midline gliomas. Gliomas in the midline of the brain belong to the most aggressive primary malignant brain cancer type. The disease is derived from glial cells, cells that form tissues that surround and protect other nerve cells found in the brain and spinal cord.
Standard therapy for midline gliomas involves neurosurgery, where feasible, followed by fractionated external beam radiotherapy. Due to location, invasiveness and low survival time in the brain, gliomas in the midline of the brain are considered part of the most lethal form of cancer.
There is evidence that H3K27M occurs mainly in midline gliomas and in young patients: about 75% thalamic tumors, about 54% brainstem tumors and 55% spinal cord tumors; 24% of pediatric gliomas and 8% of adult gliomas. The H3K27M mutation occurred in a unique spatiotemporal pattern, with midline gliomas involving the pons (i.e., DIPGs) tending to occur in pediatric patients (<18 years) and midline gliomas involving the thalamus and spinal cord tending to occur in young adult patients.
It is generally believed that the presence of the H3K27M mutation in midline gliomas confers a poorer clinical prognosis. This understanding was incorporated into the World Health Organization2016 central nervous system tumor classification of central nervous system tumors, which now defines a diffuse midline glioma with the H3K27M mutation as a new and unique disease entity. Since it is widely recognized that the prognosis of brain tumors with this mutation is disastrous, the disease is defined as grade IV regardless of histopathological characteristics.
Most of the prognostic literature for H3K27M was derived from DIPG showing the prevalence of this mutation to 70-85%. Clearly, the presence of the H3K27M mutation in the tumor of the pons confers a greatly shortened overall survival relative to a few patients without this mutation. For a smaller number of pediatric patients with glioma outside the pons, the literature is consistent with the belief that patients with the H3K27M mutation have a poor prognosis. Based on the high prevalence of the disease mutation, DIPG was considered in the art as the most robust subject of clinical experience for H3K27M glioma. Clinical trials of DIPG over decades have failed to improve outcomes and the standard of care of the 6-week radiation course remained associated with an overall survival of 9-11 months. Historically, therapeutic clinical trials in DIPG have focused on evaluating therapies that have proven effective for high-grade adult gliomas. Recent molecular analysis and emerging preclinical models of linear gliomas in H3K27M show that these tumor surfaces show distinct biological and therapeutic sensitivities relative to other adult gliomas (e.g., glioblastoma).
The H3K 27M mutant glioma is less frequent in adults compared to pediatric patients. The literature is relatively consistent with pediatric findings and appears to demonstrate the catastrophic effects of the H3K 27M mutation in adult brain tumors, particularly brain glioma, in general. The overall survival of adult patients with H3K 27M midline glioma was approximately 16 months, with studies indicating that the H3K 27M mutation at the brainstem position is associated with significantly shortened survival time.
Unlike many available therapies, one of the features that identify ONC201 as an anticancer agent in the selection process is its ability to penetrate the blood-brain barrier to address tumors present in the CNS. Subsequent animal studies showed that ONC201 rapidly crosses the blood brain barrier, reaching concentrations in the brain more than 5-fold relative to plasma and inducing downstream signaling in the brain (TRAIL-induced).
The compounds have high biological activity in the brain, show no evidence of neurotoxicity, and are potent cytotoxic to high grade gliomas in vitro, ex vivo, and in vivo. ONC201 has p53 independent activity on high-grade glioma cell lines including cell lines resistant to radiotherapy. In addition to cell lines, ONC201 showed potent anticancer activity in temozolomide-resistant primary high-grade glioma samples.
In vivo, ONC201 reduced high grade glioma xenografts against temozolomide and extended survival of mice with in situ xenografts as a single dose and combined with bevacizumab. Dramatic ONC201 single dose efficacy has also been observed in 3D neurosphere cultures of radiation and chemotherapy resistant high grade glioma cell lines as well as newly diagnosed and relapsed patient samples.
DRD2 was overexpressed in high grade gliomas. In studies using six human GBM cell lines from NCI60 cell line panels, the expression level of DRD2 correlated with cell responsiveness to ONC201 (fig. 3). Interestingly, in NCI60 and GDSC data sets, expression of the D1-like dopamine receptor DRD5, which blocks DRD2 signaling, was significantly inversely correlated with ONC201 efficacy (P <.05) (fig. 3).
In the publicly available ChIP-Seq database, components of H3 and the PRC2 methyltransferase complex inhibited by the K27M mutation were found to mark the DRD2 and DRD5 genes, respectively, in DIPG and isogenic models. Although the precise epigenetic mechanism that regulates the balance of DRD2: DRD5 expression is an active region investigated, H3K 27M glioma was hypothesized to be cultured as a chromatin landscape leading to high expression of DRD2 and suppression of DRD5 expression, which in turn may make these tumor cells more sensitive to ONC 201. ONC201 was tested against one panel of patient-derived glioma tumor sphere cultures grown in serum-free neural stem cell culture. The patient-derived lines contained five histone H3K 27M mutant DIPGs (two HIST1H3B and three H3F3A mutants), two H3F3A G34 mutant pediatric glioblastoma (one G34V, one G34R), and 7H 3 wild-type (3 pediatric, 4 adult) glioblastoma cell lines. Wild type glioma strain (median IC) with histone H3 50About 1.5 μ M, n-7 lines; p is a radical of<01) compared to ONC201 histone H3K 27M mutant (median IC)50About 0.6 μ M, n-5 lines) has more potent cytotoxicity.
In addition, DRD2 and DRD5 expression were analyzed in untreated patient glioma samples. RNASeq was performed on patient biopsies from H3K 27M mutant glioma (n ═ 8), wild-type pediatric (n ═ 3), and adult glioma (n ═ 25), H3G 34R mutant glioma (n ═ 3). DRD2 expression was significantly increased in histone H3K 27M mutant glioma tumors compared to adult and pediatric H3 wild-type tumors (p ═ 0.02). In contrast, DRD5 had low expression in all gliomas tested, whereas DRD5 expression in histone H3K 27M mutant gliomas showed a trend lower than wild-type gliomas. Thus, the DRD2 and DRD5 expression profiles of H3K 27M mutant patient gliomas are consistent with the expression signatures in preclinical models predictive of ONC201 sensitivity.
Cancer stem cells have been shown to express relatively high levels of DRD2 compared to most populations, and ONC201 is effective in depleting cancer stem cells in many malignancies. This effect may help to prolong survival of patients in phase II GBM studies of ONC201 despite the fact that many patients receive limited drug exposure (1 or 2 doses).
NK cells are known to express DRD2 and ONC201 is reported to increase NK cell pool in circulation and in tumors. More important is the activation of NK cell function recorded in vivo as well as in patient samples. This significant immunostimulatory effect may contribute to the anti-tumor activity of the compounds and is consistent with the response kinetics seen in ongoing clinical trials (i.e., long-term and delayed responses). GBM tumor microenvironments have been described as being completely immunosuppressive and several ways of stimulating immune function have been shown to affect GBM tumor cell growth.
Example 14: ONC201 in a 22 year old female with recurrent H3K 27M mutant glioblastoma.
The histone H3K 27M mutation distinguishes a subgroup of glioma among children and young adults with a devastating prognosis due to the absence of effective drug therapy. The first H3K 27M glioma patient receiving ONC201 was a 22 year old female with multifocal disease involving their thalamus, who was treated as part of a phase II recurrent glioblastoma trial in adults (NCT 02525692). The patient had recurrent glioblastoma (unmethylated MGMT, H3.3K 27M mutant) and was treated with 625mg ONC201 once every three weeks. The patient had previously progressed following previous surgery, radiation and temozolomide.
After initiation of ONC201 therapy, patients showed a persistent objective response with complete regression of thalamic lesions (fig. 20A). After 18 doses, the total tumor size regressed 96% (fig. 20B). The patient is no longer taking anti-epileptic drugs on a regular basis as before starting to take the ONC 201. This response remains persistent and patients continue to receive therapy for >1.5 years with no drug related adverse events reported. In addition to cytotoxic effects in tumor cells, DRD2 antagonism can also induce activation of NK and other immune cells. Immune induction was associated with tumor shrinkage (fig. 14). The level of immune effects in serum correlates with the kinetics of objective responses that are consistent with delayed, persistent responses.
Example 15: ONC201 in a 74 year old female with recurrent H3K 27M mutant glioblastoma.
This example provides a case study of a 74 year old female H3K 27M (unknown MGMT status) glioma patient who also participated in the phase II recurrent glioblastoma test with ONC201 mentioned in the previous example. Patients also suffer from multifocal disease and progress after first-line surgery, radiation, and temozolomide. Patients also developed progression following subsequent CCNU second line therapy. Prior to ONC201 treatment, this subject had three lesions. The first treatment assessment of the
Example 16: ONC201 treatment in 10-year-old girls with H3K 27M mutant DIPG.
In this example, 10 year old girls with H3.3K 27M mutant diffuse endogenous brain bridge glioma (DIPG) were treated once a week with 500mg of ONC 201. The subject suffered from left-sided facial paralysis and reduced hearing in the left ear. Previous therapy included 6 week radiation sessions. Radiographic evaluation of the subject tumors after 16 weeks of ONC201 therapy showed significant regression and reduction in enhancement of exogenous brain tumors (figure 16). The subject also experienced near complete regression of facial paralysis associated with cranial nerve palsy due to the location of their tumor. The subjects also tolerated the therapy well and the trial was continued.
Example 17: mutant DI with H3K 27MONC201 treatment in PG 3-year-old girls.
In this example, a 3 year old girl with H3.3K 27M mutant diffuse endogenous brain bridge glioma (DIPG) was treated once a week with 125mg of ONC 201. The subject suffered from the sixth nerve paralysis on the right and weakness in the left arm and left hand. Previous therapy included 6 week radiation sessions. Radiographic evaluation of their tumors after 6 weeks of ONC201 therapy showed stable tumor lesions (fig. 17). The subject also experienced complete regression of the unusable left arm and left hand associated with cranial nerve palsy due to the location of their tumor. The subject was fully ambulatory and well tolerated for therapy and the trial was continued.
The clinical outcome of high grade glioma with the H3K 27M mutation was clearly at a disadvantage relative to patients without the mutation. In a study of thirty-nine pediatric diffuse endogenous pontine gliomas, the overall survival of DIPG patients carrying the K27M-H3.3 mutation (n ═ 30) was worse compared to wild-type (n ═ 9) patients with this histone protein (Khoung-quant et al, neuropathology letters (2012)124: 439). Significantly, all long-term survivors were H3.3 wild-type. Surprisingly, ONC201 treatment conferred superior Progression Free Survival (PFS) in H3K 27M patients. Progression-free survival (PFS) with ONC201 treatment was determined by MRI before initiating ONC201 therapy in fifty patients with recurrent high grade glioma presented at baseline (fig. 18). Groups are divided into two groups: one group had the known H3K 27M mutation (n-15) and the other group had the wild-type or unknown H3 state (n-35). Notably, all long term progression free patients treated with ONC201 were H3K 27M patients.
Example 18: clinical evaluation of imiperidone ONC201 in recurrent glioblastoma: predictive and pharmacodynamic therapy And (4) analyzing the marker.
Imiperidone ONC201 was the first selective antagonist of the G protein-coupled receptor DRD2 for clinical oncology. ONC201 induces p 53-independent apoptosis in newly diagnosed and recurrent glioblastoma in vitro, ex vivo and in vivo. Performing a phase II clinical trial, said trial receiving every three weeks 625mg ONC201 of 17 patients with recurrent IDH1/2WT glioblastoma who were not enrolled with bevacizumab. One patient continued to have a lasting objective response that deepened over time, showing a 92% regression after 15 months of treatment. After the re-resection, another patient remained disease-free after 14 months of enrollment into this trial. Median OS was 41.6 weeks with OS12 at 35%. No drug-related SAE occurred or treatment was discontinued due to toxicity. Plasma PK was 2.6 μ g/
Example 19: ONC201 is active in glioblastoma with deregulated DRD2 pathway.
ONC201 (emilone, a selective antagonist of the G-protein coupled receptors dopamine receptors D2(DRD2) and D3(DRD 3)) showed tumor shrinkage and excellent safety profile in phase II recurrent glioblastoma clinical trials. In vitro and in vivo studies have shown the efficacy of the single agent ONC201 in a glioblastoma model (Allen et al, Science transformation medicine 5,171ra117-171ra117 (2013)). In vitro efficacy analysis of ONC201 in a collection of cancer drug sensitive Genome (GDSC) cell lines demonstrated broad anti-cancer efficacy,among them, it has high sensitivity in human brain cancer cell lines (FIG. 2). DRD2 is overexpressed in glioblastomas and DRD2 antagonism induces apoptosis in tumor cells through signaling pathways responsive to ONC 201. Investigation of the cancer genomic map (TCGA) revealed that DRD2 is highly expressed and has little genetic variation in glioblastoma relative to other dopamine receptor family members. High expression of DRD2 occurred in primary but not secondary glioblastoma and was associated with poor prognosis. Immunohistochemical analysis of tissue microarrays showed that DRD2 was overexpressed in glioblastoma compared to normal brain. DRD2 mRNA and ONC201 GI were observed between glioblastoma cell lines in NCI60 panels 50A linear relationship therebetween. Significant induction of serum prolactin (surrogate biomarker with target involvement) was detected in the ONC201 treated glioblastoma patients. Interestingly, in the NCI60 and GDSC data set, expression of the D1-like dopamine receptor DRD5, which blocks DRD2 signaling, was significantly inversely correlated with the potency of ONC201 (P<0.05). Missense DRD5 mutations that acquired resistance to ONC201 were also identified in cancer cells. Resistance can be summarized by overexpression of the mutant DRD5 gene or to a lesser extent by the wild-type gene. In summary, the DRD2 pathway is a therapeutic target for disorders in glioblastoma and contains tumor biomarkers that are sensitive to ONC 201.
Example 20: differentiated drug of first selective DRD2/3 antagonist imisterone ONC201 in clinical neurooncology Science.
The pioneer member of the omisterone compounds ONC201 has shown evidence of tumor shrinkage in patients with recurrent glioblastoma and excellent safety profiles. In this example, previously unknown binding targets of ONC201 are identified and characterized. BANDIT, a machine learning-based drug target recognition platform, predicts that ONC201 will bind with high selectivity to G protein-coupled receptors (GPCR) dopamine receptors D2(DRD2) and D3(DRD 3). DRD2 is overexpressed in glioblastomas, controls survival-promoting mechanisms, and its antagonism causes pro-apoptotic effects in malignant cells.
Example 21: the imiperidone family member ONC206 inhibits glioma stem cell maintenance.
Imiperidone selectively targets G protein-coupled receptors (GPCRs) that control key signaling pathways in various cancer cells. Aberrant GPCR overexpression has been implicated in tumorigenesis. The first generation of imiperidone ONC201, which directly antagonizes dopamine receptor D2(DRD2), continues to be evaluated in clinical trials for advanced cancer.
The method and the result are as follows: here, the ONC201 analogue ONC206, which shares the same chemical structure of the imiridone core and selective DRD2 antagonism, potently inhibited the patient-derived Glioma Stem Cell (GSC) population. Computer analysis of the glioma patient database led to an investigation of the signaling of DRD2 in gliomas; changes in DRD2 mRNA expression were directly correlated with changes in overall gene expression in the glioma patient database. The CellTiter-Glo cell viability assay showed that exposure to ONC206 preferentially abolished GSCs in a dose-dependent manner compared to differentiated glioma cells. Protein arrays of stem cell markers show protein expression down-regulated by ONC206 therapy of the carcinogenic stem cell marker in GSCs. In addition, limiting dilution assays and spheroid formation analysis in vitro showed that ONC206 prevented tumor spheroid formation and tumor growth. These observations indicate that ONC206 shows promising anti-glioma activity and warrants elucidation of downstream effects of antagonism of DRD2 signaling with ONC206 in gliomas.
Example 22: in adult H3 Clinical data using ONC201 in K27M mutant high grade glioma.
A cohort of 15 adult patients (>18 years) with recurrent H3K 27M mutant high-grade gliomas have been treated with ONC201 as participants in clinical trials or extended access protocols. Demographic and clinical characteristics are described in table 6 below. This group excludes patients who did not meet the current adult recurrent H3K 27M mutant glioma test (NCT03295396 and NCT02525692) of ONC201 (i.e., patients who received surgical intervention while taking ONC 201) or patients with leptomeningeal disease prior to receiving ONC 201. All patients received 625mg of oral ONC201 once a week, except one patient who received 625mg of oral ONC201 once every three weeks.
TABLE 6
Indicated data are reported as median values with ranges within parentheses.
Fourteen of 15 patients had undergone at least one MRI during treatment, with tumor measurements and response assessments reported by the investigator according to the RANO criteria. Four of these 14 patients had shown > 50% regression relative to baseline, which remained persistent (median follow-up 9.4 months from first dose; 3.5-27.3 months) (fig. 19). According to the RANO criteria, three patients showed partial responses, 1 patient had no measurable disease at baseline (multifocal lesions <1cm), 6 patients had stable disease, and the remaining 4 patients showed progression of disease. This resulted in a disease control rate of 71% (SD + PR + CR) and an objective response rate of 23% (PR + CR).
In addition to radiographic images, potential clinical improvements in neurological symptoms and quality of life have been reported in some patients. The radiographic and clinical benefits and short medical history of 4 patients with > 50% regression are summarized below.
One adult with recurrent glioblastoma who had previously been treated with temozolomide and radiation has shown a 96% reduction in tumor size from baseline, including complete regression of primary thalamic lesions (fig. 20). This partial response remained persistent after the first achievement of the ONC201 4.9 months after initiation of ONC201, and the patient continued to take ONC201 for a period of time>And (5) 27 months. The patient previously received and started 75mg/m25,940cGy radiation of temozolomide combination. Patient previously completed 150mg/m monthly for 4 helper cycles2Temozolomide. Because of complaints about fatigue, the dose did not rise to 200mg/m until the patient took temozolomide for the fourth cycle2. The patient developed progression and began to take 625mg of ONC201 once every three weeks.
Another adult with recurrent H3K 27M mutant glioma has shown a 60% reduction in tumor size from baseline (fig. 21), including complete regression of the primary thalamic lesion. This patient, 38 years old, was diagnosed with grade 3 degenerative astrocytomas, of which the left thalamus had the H3K 27M mutation. The patient began receiving temozolomide (75 mg/m) 2Day, 42 consecutive days) and radiation (60 Gy). In view of their disease progression, patients need to accelerate the split up from 200cGy to 250cGy daily dose after 3,000 cGy. The patient completed irradiation of the left thalamus. The patient also completed temozolomide for 6 weeks, at completionThe final 6 th week was completed after the accelerated radiation schedule. The patient takes 150mg/m2The dose of (A) is restarted with temozolomide, and after one month the dose is increased to 200mg/m2For about four months. MRI assessment shows disease progression. The patient started at 110mg/m2The dose of (a) is CCNU. After 2 cycles, MRI evaluation showed further progression of invasive edema and small contrast enhanced lesions with tumor spectra and perfusion characteristics without new space effects or hernia formation. The patient began taking ONC201 via a sympathic emergency use protocol and received 625mg ONC201 orally once a week. At baseline, this patient will take 60mg hydrocortisone plus 10mg prednisone daily and will take up to 8mg dexamethasone daily to treat headache. After the initial ONC 2016 week, the patient's first MRI showed improvement in left atrial week enhancement and edema and 34% total regression. Subsequent MRI has shown regression>50%, which represents a partial response according to the RANO standard. Patients have reported potential clinical improvement in disease-related symptoms such as headache, nausea, and right side numbness. The patient continues to take ONC201 for a period of time >9.1 months.
Another adult with recurrent H3K 27M mutant has shown a 53% reduction in tumor volume from baseline according to RANO 15 weeks after initiation of ONC201 administration (fig. 22). This patient was diagnosed with WHO grade IV diffuse midline glioma. The patient was irradiated with 6,000cGy conjugated temozolomide 75mg/m2Treatment was performed for about five weeks. The patient began taking 625mg ONC201 orally once a week. Patients began (every three weeks) to take avastin to gradually reduce steroids. The patient continues to take ONC201 for a period of time>3.5 months.
It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the exemplary embodiments shown and described, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims. For example, the specific features of the exemplary embodiments may or may not be part of the claimed invention and features of the disclosed embodiments may be combined. The terms "a" and "the" are not limited to one element but are to be construed to mean "at least one" unless specifically indicated herein.
It is to be understood that the figures and descriptions may have been simplified to focus on elements that are relevant for a clear understanding, while eliminating, for purposes of clarity, other elements that those skilled in the art will appreciate may also include a portion of the present invention. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.
Furthermore, to the extent that the method does not rely on the particular order of steps set forth, such particular order should not be construed as limitations on the claims. The claims directed to the method should not be limited to the performance of the steps in the order written, and one skilled in the art can readily appreciate that the order may be varied and still remain within the spirit and scope of the present invention.
All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
- 上一篇：一种医用注射器针头装配设备
- 下一篇：异喹啉衍生物用于伤口愈合的新颖用途