Method for treating acute myeloid leukemia

文档序号：1957521 发布日期：2021-12-10 浏览：14次中文

阅读说明：本技术 治疗急性髓性白血病的方法 (Method for treating acute myeloid leukemia ) 是由 M·L·威特尔 A·J·德什潘德 K·O·巴博萨·圭拉于 2020-01-15 设计创作，主要内容包括：本发明描述的一方面包括治疗有需要的受试者的急性髓性白血病(AML)的方法,包括向受试者施用有效量的小分子微管蛋白聚合抑制剂化合物。更具体地,本发明描述的另一方面包括用于治疗有需要的受试者的急性髓性白血病的方法,包括向受试者组合施用有效量的本发明所述的小分子微管蛋白聚合抑制剂化合物和化学治疗剂。(One aspect described herein includes a method of treating Acute Myeloid Leukemia (AML) in a subject in need thereof comprising administering to the subject an effective amount of a small molecule tubulin polymerization inhibitor compound. More specifically, another aspect described herein includes a method for treating acute myeloid leukemia in a subject in need thereof, comprising administering to the subject an effective amount of a small molecule tubulin polymerization inhibitor compound of the invention in combination with a chemotherapeutic agent.)

1. A method of treating acute myeloid leukemia in a subject in need thereof, comprising administering to the subject an effective amount of 5-fluoro-2- (6-fluoro-2-methyl-1H-benzo [ d]Imidazol-1-yl) -N⁴- [4- (trifluoromethyl) phenyl group]Pyrimidine-4, 6-diamine having the following structure:

or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

2. The method of claim 1, wherein the acute myeloid leukemia is CALM-AF 10-mediated acute myeloid leukemia.

3. The method of claim 1, further comprising administering to the subject an effective amount of 5-fluoro-2- (6-fluoro-2-methyl-1H-benzo [ d ] in combination]Imidazol-1-yl) -N⁴- [4- (trifluoromethyl) phenyl group]A pyrimidine-4, 6-diamine or a pharmaceutically acceptable salt or pharmaceutical composition thereof and an effective amount of one or more chemotherapeutic agents.

4. The method according to claim 3, wherein the one or more chemotherapeutic agents is 4-chlorophenyl (S) -6-chloro-1- (4-methoxyphenyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole-2-carboxylate, having the following structure of formula (II):

Technical Field

The present invention describes a method for treating Acute Myeloid Leukemia (AML) in a subject in need thereof comprising administering to the subject an effective amount of a small molecule tubulin polymerization inhibitor compound. More specifically, described herein is a method for treating AML in a subject in need thereof, comprising administering to the subject an effective amount of a small molecule tubulin polymerization inhibitor compound, alone or in combination with a chemotherapeutic agent.

Background

Disease recurrence is a major problem in AML treatment, and elderly patients with p53 mutant-mediated AML have a very high risk of recurrence, particularly those with complex karyotypes (60% -80%) and treatment-related AML (30%), whose tumor suppressor p53 is frequently mutated (Nishida Y, et al. the novel BMI-1inhibitor PTC596 descending regulations MCL-1and indeces p53-independent mitochondrial apoptosis in enzyme granular deficiency promoter cells; Blood Cancer j.,2017Feb 17; 7(2): e 527; doi: 10.1038/bcj.2017.8). The 5-year survival rate of patients over 60 years old is only 3-8%.

In young patients, AML is in some cases caused by genomic translocation events that produce oncogenic fusion proteins (great and Wiemels 2003). the t (10; 11) (p 13-14; q14-21) translocation is a recurrent equilibrium translocation observed in AML, which produces CALM-AF10 fusion protein. Standard chemotherapy is generally not very effective in treating patients with CALM-AF10 fusion protein. Since there is currently no clinical-grade targeted therapy for this disease subtype, the prognosis for those patients carrying the CALM-AF10 fusion protein is particularly poor. CALM-AF10 fusion protein is more common in children and young adults, with a median age of 20 years. The 5-year survival rate of young patients is only 30-40%.

Therefore, there is an urgent need to identify clinical-grade targeted therapies for the treatment of dysregulated CALM-AF10 positive leukemia.

Disclosure of Invention

The compound 1 is a small molecular compound and is named as 5-fluoro-2- (6-fluoro-2-methyl-1H-benzo [ d]Imidazol-1-yl) -N⁴- [4- (trifluoromethyl) phenyl group]Pyrimidine-4, 6-diamine having the following structure:

or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of leukemia.

One aspect described herein is a method of treating Acute Myeloid Leukemia (AML) in a subject in need thereof comprising administering to the subject an effective amount of compound 1.

Another aspect described herein is a method of treating AML in a subject in need thereof comprising administering to the subject an effective amount of compound 1in combination with a chemotherapeutic agent.

Another aspect described herein is the use of compound 1in the manufacture of a medicament for treating AML in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

One aspect described herein is a method of treating CALM-AF 10-mediated Acute Myeloid Leukemia (AML) in a subject in need thereof, comprising administering to the subject an effective amount of compound 1.

Another aspect described herein is a method of treating CALM-AF 10-mediated AML in a subject in need thereof, comprising administering to the subject an effective amount of compound 1in combination with a chemotherapeutic agent.

Another aspect described herein is the use of compound 1in the manufacture of a medicament for treating CALM-AF 10-mediated AML in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

One aspect described herein is a method of treating Acute Myeloid Leukemia (AML) mediated by a p53 mutant in a subject in need thereof, comprising administering to the subject an effective amount of compound 1.

Another aspect described herein is a method of treating AML mediated by a p53 mutant in a subject in need thereof, comprising administering to the subject an effective amount of compound 1in combination with a chemotherapeutic agent.

Another aspect described herein is the use of compound 1in the manufacture of a medicament for treating AML mediated by a p53 mutant in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

One aspect described herein is a method of treating acute myeloid leukemia in a subject in need thereof, comprising administering to the subject an effective amount of 5-fluoro-2- (6-fluoro-2-methyl-1H-benzo [ d]Imidazol-1-yl) -N⁴- [4- (trifluoromethyl) phenyl group]Pyrimidine-4, 6-diamine having the following structure:

or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

Another aspect described herein is a method of treating acute myeloid leukemia, wherein the acute myeloid leukemia is CALM-AF10 mediated acute myeloid leukemia.

Another aspect described herein is a method of treating acute myeloid leukemia, wherein the acute myeloid leukemia is p53 mutant mediated acute myeloid leukemia.

Another aspect described herein is the combined administration to a subject of an effective amount of 5-fluoro-2- (6-fluoro-2-methyl-1H-benzo [ d]Imidazol-1-yl) -N⁴- [4- (trifluoromethyl) phenyl group]Pyrimidine-4, 6-diamine or a pharmaceutically acceptable salt or pharmaceutical composition thereof and an effective amount of one or more chemotherapeutic agents.

In another aspect of the invention described herein, when compound 1 is administered in combination with an effective amount of one or more chemotherapeutic agents, the one or more chemotherapeutic agents is 4-chlorophenyl (S) -6-chloro-1- (4-methoxyphenyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole-2-carboxylate (compound 2), which has the following structure of formula (ii):

drawings

Figure 1 shows the survival curves of the P31-Fujioka cell line xenograft tumor NSG/SRM3 mouse model in vivo after 34 days of treatment with compound 1and with vehicle (n-5 mice per group, P < 0.002).

Figure 2 shows the percent weight change of AML NSG [ NOD (non-obese diabetic) SCID (severe combined immunodeficiency) gamma ] mouse model in vivo after 75 days of treatment with compound 1and vehicle (vehicle group n ═ 5, compound 1 group n ═ 2).

Figure 3 shows the survival curves of the AML NSG mouse model in vivo after 75 days of treatment with compound 1and vehicle (vehicle group n-5, compound 1 group n-2).

Figure 4 shows the percent body weight change of the AML NSG mouse model in vivo after 80 days of treatment with the combination of compound 1and compound 2 and with vehicle, compound 1 alone and compound 2 alone (n ═ 2 in the combination and compound 1 alone groups and n ═ 5 in the vehicle and compound 2 alone groups).

Figure 5 shows survival curves of AML NSG mouse model in vivo after 80 days of treatment with combination of compound 1and compound 2 and with vehicle, compound 1 alone and compound 2 alone.

FIG. 6 shows survival curves of a mouse model of the ALL (acute lymphocytic leukemia) MOLT-4(CD3 deficient) xenograft tumor in vivo, NSG, after 160 days of treatment with Compound 2 and with vehicle, Compound 1, Doxorubicin (Dox) and Cytarabine (Ara-C). Including various dosing regimens.

Detailed Description

One aspect described herein is the use of compound 1, compound 1 being a small molecule having the name 5-fluoro-2- (6-fluoro-2-methyl-1H-benzo [ d ]]Imidazol-1-yl) -N⁴- [4- (trifluoromethyl) phenyl group]Pyrimidine-4, 6-diamine having the following structure:

or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of leukemia. Compound 1and its method of preparation are disclosed in international application publication No. WO2014/081906 (referenced as compound 109), which is incorporated herein by reference.

One aspect described herein is a method of treating Acute Myeloid Leukemia (AML) in a subject in need thereof comprising administering to the subject an effective amount of compound 1.

Another aspect described herein is the use of compound 1in the manufacture of a medicament for treating CALM-a 10-mediated AML in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

Another aspect described herein is a method of treating acute myeloid leukemia, wherein the acute myeloid leukemia is CALM-AF10 mediated acute myeloid leukemia.

Another aspect described herein is a method of treating acute myeloid leukemia, wherein the acute myeloid leukemia is p53 mutant mediated acute myeloid leukemia.

international application publication No. WO2005/089764, which is incorporated herein by reference, provides a method for the preparation of Compound 2. Compound 2 is also described in U.S. Pat. No. 7,601,840 (corresponding International publication No. WO 2005/089764); U.S. Pat. No. 7,767,689 (corresponding International publication No. WO 2006/113703); international application publication No. WO 2010/138758; U.S. Pat. No. 8,076,352 (corresponding International publication No. WO 2008/127715); us patent 8,076,353; us patent 8,367,694; U.S. publication No. 2010/0158858 (corresponding international application publication No. WO2008/127714), which are also incorporated herein by reference.

Definition of

In the present invention, the term "about" refers to a range around a given value, where the resulting value is substantially the same as the value explicitly recited. In one aspect, "about" means within 25% of a given value or range. For example, the term "about 70 wt%" includes at least all values from 52 wt% to 88 wt%. In another aspect, the term "about" means within 10% of a given value or range. For example, the term "about 70 wt%" includes at least all values from 63 wt% to 77 wt%. In a third aspect, the term "about" means within 7% of a given value or range. For example, the term "about 70 wt%" includes at least all values from 65 wt% to 75 wt%. Concentrations, amounts, cell numbers, percentages, and other numerical values may be expressed herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

In the present invention, the terms "methods of treatment (therapies)" and "therapy (therapy)" refer to any regimen, method, composition, formulation and/or medicament useful for preventing, treating, managing or ameliorating a condition or disorder or one or more symptoms thereof (e.g., acute myeloid leukemia or one or more symptoms thereof or one or more disorders associated therewith; CALM-AF 10-mediated acute myeloid leukemia or one or more symptoms thereof or one or more disorders associated therewith; or p53 mutant-mediated acute myeloid leukemia or one or more symptoms thereof or one or more disorders associated therewith).

In certain aspects, the terms "method of treatment" and "therapy" refer to drug therapy, such as chemotherapy, adjuvant therapy, radiation therapy, surgical therapy, biological therapy, supportive therapy, antiviral therapy, and/or other therapies useful for treating, controlling, preventing, or ameliorating a disorder or one or more symptoms thereof (e.g., acute myeloid leukemia or one or more symptoms thereof or one or more disorders associated therewith). In certain aspects, the term "therapy" refers to a therapy other than compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In particular aspects, "additional therapy" and "additional treatment methods" refer to therapies other than treatment with compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In particular aspects, the therapy comprises the use of compound 1 as an adjunct therapy. For example, compound 1 is administered in combination with a drug therapy, such as chemotherapy, biological therapy, surgical therapy, supportive therapy, antiviral therapy, and/or other therapies useful for treating, controlling, preventing, or ameliorating the condition or disorder or one or more symptoms thereof (e.g., acute myeloid leukemia or one or more symptoms thereof or one or more conditions associated therewith).

In the present invention, the term "human infant" refers to a human from newborn to the age of 1 year.

In the present invention, the term "human infant" refers to a human with an age of 1 to 3 years.

In the present invention, the term "human child" refers to a person aged from 1 to 18 years.

In the present invention, the term "human adult" refers to a person aged 18 years or older.

In the present invention, the term "middle aged human" refers to a human between the ages of 30 and 64.

In the present invention, the term "elderly" refers to people aged 65 years or older.

In the present invention, the term "subject" refers to an individual receiving treatment as described herein, and in particular aspects, the individual is a human.

In the present invention, the term "acute myeloid leukemia" generally refers to acute myeloid leukemia as described herein. In particular aspects, the general term leukemia may also be used to refer to acute myeloid leukemia, without specifically using the term acute myeloid leukemia. In another particular aspect, the term acute myeloid leukemia can also be used to refer to CALM-AF 10-mediated AML or p53 mutant-mediated AML, without specifically using the term CALM-AF 10-mediated AML or p53 mutant-mediated AML.

In the present invention, the term "effective amount" in the context of administering compound 1 to a subject with acute myeloid leukemia refers to a dose of compound 1 that produces a beneficial or therapeutic effect. In particular aspects, an "effective amount" of compound 1 refers to an amount of compound 1 sufficient to achieve at least one, two, three, four, or more of the following beneficial or therapeutic effects: (i) inhibiting acute myeloid leukemia; (ii) resolution of acute myeloid leukemia; (iii) eradicating, eliminating or completely relieving acute myeloid leukemia; (iv) preventing the development or onset of one or more symptoms associated with acute myeloid leukemia; (v) reducing or ameliorating the severity of one or more symptoms associated with acute myeloid leukemia; (vi) reducing the number of one or more symptoms associated with acute myeloid leukemia; (vii) ameliorating the severity of one or more symptoms associated with acute myeloid leukemia; (viii) reducing the duration of one or more symptoms associated with acute myeloid leukemia; (ix) preventing the recurrence of one or more symptoms associated with proliferation or acute myeloid leukemia; (x) The mortality rate is reduced; (xi) Increasing subject survival; (xii) Improving the survival rate without recurrence; (xiii) Increasing the number of acute myeloid leukemia subjects in remission; (xiv) Reducing subject hospitalization; (xv) The hospitalization time is shortened; (xvi) The hospitalization rate is reduced; (xvii) Increasing survival of the subject; (xviii) Improving asymptomatic survival in subjects with acute myeloid leukemia; (xix) Extending remission of acute myeloid leukemia in the subject; (xx) Improving quality of life (QOL), assessed by methods known in the art, such as QOL questionnaires and the like; (xxi) Reduced proliferation caused by administration of compound 1 prior to treatment with another chemotherapeutic agent; (xxii) Reduced proliferation caused by administration of compound 1 after administration of another chemotherapeutic agent; (xxiii) Reduced proliferation caused by administration of compound 1and another chemotherapeutic agent in combination therapy; (xxiv) The additional antiproliferative effect of administering compound 1 with another chemotherapeutic agent in combination therapy; (xxv) The synergistic antiproliferative effect of administering compound 1 with another chemotherapeutic agent in combination therapy; (xxvi) Decreased proliferation caused by administration of compound 1 prior to radiation therapy; (xxvii) Decreased proliferation caused by administration of compound 1 after radiation therapy; (xxviii) Reduced proliferation caused by administration of compound 1in combination therapy with radiation therapy; (xxix) Reduced proliferation caused by administration of compound 1 prior to surgical treatment; (xxx) Reduced proliferation caused by administration of compound 1in combination therapy with surgical treatment; (xxxi) Administering compound 1 with palliative therapy to enhance or improve the therapeutic effect; (xxxii) Reducing plasma concentration of BMI-1in a subject with acute myeloid leukemia; (xxxiii) Reducing circulating proliferating cells in plasma of the acute myeloid leukemia subject; (xxxiv) An alteration (e.g., a decrease or an increase) in the concentration of an acute myeloid leukemia biomarker (e.g., BMI-1, tubulin polymerization, apoptosis marker or tissue, etc.) in the plasma of an acute myeloid leukemia subject; (xxxv) A decrease in BMI-1 concentration in a biological sample (e.g., plasma, serum, urine, or any other biological fluid) of an acute myeloid leukemia subject; (xxxvi) The decrease in the number of proliferating cells after administration of the treatment method according to the invention is measured by conventional methods that can be used by the person skilled in the art, for example: magnetic Resonance Imaging (MRI), dynamic contrast enhanced MRI (DCE-MRI), X-ray, Computed Tomography (CT), Positron Emission Tomography (PET), 7-ADD fluorescence, or DAPI fluorescence; (xxxvii) The maintenance of the proliferative cell count after administration of the treatment methods described herein is measured by conventional methods available to those skilled in the art, such as: magnetic Resonance Imaging (MRI), dynamic contrast enhanced MRI (DCE-MRI), X-ray, Computed Tomography (CT), Positron Emission Tomography (PET), 7-ADD fluorescence, or DAPI fluorescence; alternatively, (xxxviii) there is no increase or a less than expected increase in the proliferation cell count following administration of a treatment method described herein, as measured by conventional methods available to those skilled in the art, for example: magnetic Resonance Imaging (MRI), dynamic contrast enhanced MRI (DCE-MRI), X-ray, Computed Tomography (CT), Positron Emission Tomography (PET), 7-ADD fluorescence, or DAPI fluorescence.

In the present invention, the term "within 24 hours" refers to maintaining a condition for a period of time, e.g., determining an effective amount of compound 1 when the mean plasma concentration of compound 1 is reached and maintained for a plurality of 24 hours. In other words, the mean plasma concentration of compound 1 may be achieved within a suitable time, which may be greater than or less than 24 hours.

In the present invention, the term "treatment method according to the present invention" refers to a method for treating or improving acute myeloid leukemia in a subject in need thereof using compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof as a tubulin polymerization inhibitor, comprising administering an effective amount of compound 1 to the subject.

In one aspect of the treatment described herein, the use or method of use of compound 1 includes a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect of the treatment described herein, the use or method of use of compound 1 includes the use or method of use of compound 1, a pharmaceutically acceptable salt or pharmaceutical composition of compound 1, or a combination of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof and another chemotherapeutic agent. Wherein the combination has a synergistic antiproliferative activity. In another aspect, the other chemotherapeutic agent inhibits tubulin polymerization. In another aspect, the other chemotherapeutic agent inhibits the functional activity of BMI-1.

In the present invention, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including inorganic acids and bases and organic acids and bases; see, for example: remington's Pharmaceutical Sciences,18^theds, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy,19^th eds,Mack Publishing,Easton PA(1995)。

In the present invention, the term "compound 1" means 5-fluoro-2- (6-fluoro-2-methyl-1H-benzo [ d ]]Imidazol-1-yl) -N⁴- [4- (trifluoromethyl) phenyl group]Pyrimidine-4, 6-diamine or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In various aspects, the term "compound 1" refers to compound 109 disclosed in international application publication No. WO2014/081906, which is incorporated herein by reference.

Application method

By mechanistic studies, without being bound by theory, compound 1 has been shown to inhibit microtubule polymerization while avoiding the most debilitating toxicity of other such drugs. In addition, compound 1, either additively or synergistically with standard clinical protocols, can produce potent and durable cancer regression.

As discussed herein, compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof is a small molecule inhibitor of tubulin polymerization for use in treating or ameliorating acute myeloid leukemia in a subject in need thereof, comprising administering to the subject an effective amount of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In one aspect of the uses or methods of use described herein, the use or method of use of compound 1 includes a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect of the uses or methods of use described herein, the use or method of use of compound 1 includes the use or method of use of compound 1, the use or method of use of a pharmaceutically acceptable salt or pharmaceutical composition of compound 1, or the use or method of use of a combination of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof and another chemotherapeutic agent. Wherein the combination has a synergistic antiproliferative activity. In another aspect, the other chemotherapeutic agent inhibits tubulin polymerization. In another aspect, the other chemotherapeutic agent inhibits the functional activity of BMI-1.

In one aspect, the invention features methods of inhibiting or reducing tubulin polymerization, which may also indirectly inhibit BMI-1 function, to induce cell cycle arrest in proliferating cells or cell lines.

In another aspect, a method of inhibiting or reducing tubulin polymerization and indirectly inhibiting BMI-1 function to induce cell cycle arrest in a proliferating cell or cell line comprises contacting compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof with a proliferating cell or cell line, wherein the proliferating cell or cell line cell may be immature or has been shown to be affected by inhibition or reduction of tubulin polymerization and BMI-1 function.

As shown in the mouse and human models described in the present invention, compound 1 surprisingly attenuated leukemia in CALM-AF 10-mediated AML in vitro and in vivo. These data, together with the safety demonstrated as an anti-cancer agent in clinical development, confirm the clear rationale for developing compound 1 for the treatment of CALM-AF10 mediated AML, either alone or in combination with standard-of-care chemotherapy.

In AML mediated by p53 mutant (see Nishida et al)Compound 1 was shown to reduce MCL-1 expression and trigger several molecular events consistent with induction of mitochondrial apoptosis: mitochondrial membrane potential disappearance, BAX conformational change, caspase 3 cleavage and phosphatidylserine eversion. Concomitant with subject-derived CD34⁺CD38^low/-Reduction of MCL-1and phosphorylated AKT in stem/progenitor cells, apoptosis was induced in a p53-independent manner. The mouse xenograft model also showed in vivo anti-leukemic activity, inhibiting leukemic cell growth in vivo while retaining normal hematopoietic cells. These data also indicate that compound 1 can be used alone or in combination with standard-of-care chemotherapy for the treatment of AML mediated by p53 mutants.

In another aspect, non-limiting examples of such cells or cell lines are selected from HL-60, HeLa, HT1080, HCT116, HEK293, NCI H460, U-87MG, ASPC-1, PL-45, HPAF-2, PC-3, MDA-MB-231, MDA-MB-468, A431, SNU-1, AGS, Kato III, A549, Calu-6, A375, SY5Y, SKOV3, Capan-1, sNF96.2, TIVE-L1, TIVE-L2, LNCaP, and the like. In a more specific aspect, the cell or cell line can be an acute myeloid leukemia cell.

In one aspect, the invention features a method of inhibiting or reducing tubulin polymerization and BMI-1 function in a subject having acute myelogenous leukemia in need thereof, comprising administering to the subject an effective amount of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In a particular aspect, a subject diagnosed with acute myeloid leukemia can be treated with a chemotherapeutic agent for inhibiting or reducing tubulin polymerization.

In a particular aspect, a subject diagnosed with acute myeloid leukemia can be treated with a chemotherapeutic agent for inhibiting or reducing BMI-1 function.

In a particular aspect, the methods of inhibiting or reducing tubulin polymerization described herein are capable of inhibiting or reducing tubulin polymerization by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% as compared to the amount of compound 1 administered to the subject prior to the administration of the composition to the subject, as assessed by methods known in the art.

In a particular aspect, a method of inhibiting or reducing BMI-1 function described herein is capable of inhibiting or reducing BMI-1 function by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% as compared to prior to administration of compound 1 to a subject, as assessed by methods well known in the art.

In a particular aspect, the methods of inhibiting or reducing tubulin polymerization described herein are capable of inhibiting or reducing tubulin polymerization in the range of about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, as compared to prior to administration of compound 1 to a subject, and the methods are evaluated as known in the art.

In a particular aspect, the methods of inhibiting or reducing BMI-1 function described herein are capable of inhibiting or reducing BMI-1 function in a range from about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, as compared to prior to administration of compound 1 to a subject, and the methods are evaluated as known in the art.

In a particular aspect, the methods of the invention for inhibiting or reducing tubulin polymerization inhibit proliferation or reduce proliferation of a population of proliferating cells or cell lines in vitro or in vivo by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% as compared to prior to administration of compound 1 to a subject, and the methods are well known in the art.

In a particular aspect, the methods of inhibiting or reducing BMI-1 function described herein are capable of inhibiting proliferation or reducing proliferation of a population of proliferating cells or cell lines in vitro or in vivo by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% as compared to prior to administration of compound 1 to a subject, as assessed by methods well known in the art.

In a particular aspect, the methods of the invention for inhibiting or reducing tubulin polymerization can inhibit proliferation or reduce a population of proliferating cells or cell lines in vitro or in vivo in a range from about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, as compared to prior to administration of compound 1 to a subject, and the methods are evaluated as known in the art.

In a particular aspect, the methods of the invention for inhibiting or reducing BMI-1 function are capable of inhibiting proliferation or reducing a population of proliferating cells or cell lines in vitro or in vivo in a range from about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, as compared to prior to administration of compound 1 to a subject, the methods evaluated are methods well known in the art.

In various aspects, the methods of the invention for inhibiting or reducing tubulin polymerization reduce the expression of GTP-bound α β -tubulin subunits available for microtubule assembly in a subject, as assessed by methods known in the art, such as ELISA.

In various aspects, the methods of inhibiting or reducing BMI-1 function described herein reduce the plasma concentration of BMI-1in a subject, and the methods of assessment are well known in the art, such as ELISA.

In one aspect, the invention features a method for preventing, treating or ameliorating acute myeloid leukemia in a subject in need thereof, comprising administering an amount of compound 1 effective to inhibit or reduce tubulin polymerization in the subject.

In one aspect, the invention features a method for preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, comprising administering an amount of compound 1 effective to inhibit or reduce BMI-1 function in the subject.

In a particular aspect, the methods of the invention for preventing, treating or ameliorating acute myeloid leukemia in a subject in need thereof are capable of inhibiting or reducing tubulin polymerization by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% as compared to the method of evaluating as known in the art prior to administering compound 1 to the subject.

In a particular aspect, the methods of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, as described herein, are capable of inhibiting or reducing BMI-1 function by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% as compared to prior to administration of compound 1 to the subject, as assessed by methods well known in the art.

In a particular aspect, the methods of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof described herein are capable of inhibiting or reducing tubulin polymerization in the range of about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, as compared to prior to administration of compound 1 to the subject, the methods evaluated are methods well known in the art.

In a particular aspect, the methods of preventing, treating, or ameliorating acute myeloid leukemia described herein can inhibit or reduce BMI-1 function in a range from about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, as compared to prior to administration of compound 1 to a subject in need thereof, the methods evaluated are methods well known in the art.

In various aspects, the methods of the invention for preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, reduces the subject's BMI-1 plasma concentration, and the methods of assessment are well known in the art, such as ELISA.

In a particular aspect, the methods of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, as described herein, are capable of inhibiting proliferation or reducing proliferation of a population of proliferating cells or cell lines in a subject by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% in vitro or in vivo as compared to the method of evaluating as known in the art prior to administering compound 1 to the subject.

In a particular aspect, the methods of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof described herein are capable of inhibiting proliferation or reducing a population of proliferating cells or cell lines in a subject in vitro or in vivo in a range from about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or about 40% to about 100%, or any range therebetween, as compared to prior to administration of compound 1 to the subject, as evaluated methods well known in the art.

In various aspects, the methods of the invention for preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, inhibits proliferation or reduces a population of proliferating cells or cell lines in the subject in vitro or in vivo, and the methods of assessment are well known in the art, such as ELISA.

In one aspect, the invention features a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, comprising administering compound 1in combination with another therapy (e.g., one or more additional therapies that do not include compound 1 or that contain a different anti-proliferative agent) in an amount effective to inhibit proliferation or reduce a population of proliferating cells or cell lines in or out of the subject.

Such methods include administering compound 1 prior to, concurrently with, or after administration of the additional therapy. In certain aspects, such methods have additive or synergistic effects.

In a specific aspect, the invention provides a method of preventing, treating or ameliorating acute myeloid leukemia in a subject in need thereof comprising administering to the subject in need thereof an effective amount of compound 1and an effective amount of another therapy.

In one aspect, the methods of the invention comprise methods that may be provided according to the invention to prevent, treat or ameliorate hematological cancers, including but not limited to acute myeloid leukemia.

In a particular aspect, examples of hematological cancers that can be prevented, treated, or ameliorated according to the methods provided herein include, but are not limited to, acute myeloid leukemia.

In one aspect, the present invention provides a method for preventing, treating or ameliorating acute myeloid leukemia, comprising: (a) administering one or more doses of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a subject in need thereof; (b) monitoring the concentration of certain biomarkers before and/or after step (a).

In a particular aspect, monitoring step (b) is performed before and/or after a number of doses (e.g., 1, 2, 4,6, 8, 10, 12, 14, 15, or 29 doses, or more doses; 2-4 doses, 2-8 doses, 2-20 doses, or 2-30 doses), or before or after a period of time (e.g., 1, 2, 3,4, 5, 6, or 7 days; or 1, 2, 3,4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks) during which compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered.

In a particular aspect, one or more of these monitoring parameters is detected prior to administering compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to the subject.

In a particular aspect, a decrease in proliferation of the proliferating cell or cell line population in vitro or in vivo following administration of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, indicates that the course of treatment is effective for preventing, treating, or ameliorating acute myeloid leukemia.

In a particular aspect, a change in proliferation of the proliferating cell or cell line population in vitro or in vivo following administration of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, can indicate that the dosage, frequency, and/or length of administration of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, can be adjusted (e.g., increased, decreased, or maintained).

In a particular aspect, the concentration of certain biomarkers in a biological sample is monitored before, during, and/or after a course of treatment for acute myeloid leukemia involving administration of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a subject.

The dosage, frequency and/or length of administration of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, administered to a subject may be altered by the proliferation of proliferating cells or cell line populations in vitro or in vivo. Alternatively, a change in these monitored parameters (e.g., the concentration of certain biomarkers) may indicate that a course of treatment involving administration of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof is effective to prevent, treat or ameliorate acute myeloid leukemia.

The concentration of certain biomarkers in a subject can be detected by any technique known to those skilled in the art, and in certain aspects, methods for detecting the concentration of certain biomarkers in a subject include obtaining a biological sample (e.g., a tissue or fluid sample) from a subject, detecting the concentration of a biomarker (e.g., from plasma, serum, urine, or any other biological fluid) in a biological sample that has been subjected to certain types of processing (e.g., centrifugation), detecting using immunological techniques, such as ELISA.

In a particular aspect, the ELISA of the invention can be used to detect the concentration of a biomarker in a biological sample (e.g., from plasma, serum, urine, or any other biological fluid) that has undergone some type of processing (e.g., centrifugation). Other techniques known in the art that can be used to detect biomarker concentrations in biological samples include multiplex assays or proteomic analysis.

In particular aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia alleviate or control one, two, or more symptoms associated with acute myeloid leukemia. Alleviating or controlling one, two or more symptoms of acute myeloid leukemia can be used as a clinical endpoint for the prevention, treatment or amelioration of the efficacy of acute myeloid leukemia by Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia reduce the duration and/or severity of one or more symptoms associated with acute myeloid leukemia. In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia inhibit the onset, development, and/or recurrence of one or more symptoms associated with acute myeloid leukemia. In certain aspects, the methods of treating acute myeloid leukemia provided by the present invention reduce the number of symptoms associated with acute myeloid leukemia.

In certain aspects, the methods provided herein for preventing, treating or ameliorating acute myeloid leukemia extend or delay the G1/S phase or the G1/S end-stage of the cell cycle (i.e., the period between the end checkpoint (stationary phase or pre-DNA synthesis) and the early stage of DNA synthesis). In other aspects, the methods provided herein for preventing, treating or ameliorating acute myeloid leukemia extend or delay the S phase or G2/M phase of the cell cycle (i.e., the period between DNA synthesis and early mitotic phase).

In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia reduce, ameliorate, or reduce the severity of acute myeloid leukemia and/or one or more symptoms thereof. In other aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia reduce the number of hospitalizations (e.g., the number and duration of hospitalizations) of a subject diagnosed with acute myeloid leukemia.

In certain aspects, the methods provided herein increase the survival of a subject diagnosed with acute myeloid leukemia. In particular aspects, the methods provided herein increase the survival of a subject diagnosed with acute myeloid leukemia by about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, or about 12 months or more.

In a particular aspect, the present invention provides methods for preventing, treating or ameliorating acute myeloid leukemia that inhibit or reduce the development of acute myeloid leukemia or one or more symptoms associated therewith. In a particular aspect, the present invention provides methods for preventing, treating or ameliorating acute myeloid leukemia that can enhance or enhance the efficacy of other therapeutic approaches (e.g., anti-cancer agents, radiation therapy, drug therapy, such as chemotherapy, anti-androgen therapy, or surgical therapy). In certain aspects, the methods provided herein for preventing, treating or ameliorating acute myeloid leukemia involve the use of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof as an adjunct therapy.

In a particular aspect, the present invention provides methods for preventing, treating or ameliorating acute myeloid leukemia that reduce the mortality of a subject diagnosed with acute myeloid leukemia. In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia increase the number of subjects in remission or reduce the rate of hospitalization. In other aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia prevent the progression, onset, or development of one or more symptoms associated with acute myeloid leukemia.

In a particular aspect, the present invention provides methods for preventing, treating or ameliorating acute myeloid leukemia that increase survival in asymptomatic subjects with acute myeloid leukemia. In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia do not cure acute myeloid leukemia in a subject, but can prevent the development or progression of the disease. In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia improve the quality of life of a subject.

In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia increase survival in cancer-free subjects with acute myeloid leukemia. In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia improve relapse-free survival. In certain aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia increase the number of subjects in remission. In other aspects, the methods provided herein for preventing, treating, or ameliorating acute myeloid leukemia extend the remission period of the subject.

Treatment of populations

In certain aspects, a subject treated for acute myeloid leukemia according to the methods provided herein is a human having or diagnosed with acute myeloid leukemia. In other aspects, the subject being treated for acute myeloid leukemia according to the methods provided herein is a human susceptible to or susceptible to acute myeloid leukemia. In certain aspects, a subject treated for acute myeloid leukemia according to the methods provided herein is a human at risk of developing acute myeloid leukemia.

In one aspect, the subject being treated for acute myeloid leukemia according to the methods provided herein is a human infant. In another aspect, the subject being treated for acute myeloid leukemia according to the methods provided herein is a human young child. In another aspect, the subject treated for acute myeloid leukemia according to the methods provided herein is a human child. In another aspect, the subject treated for acute myeloid leukemia according to the methods provided herein is a human adult. In another aspect, the subject treated for acute myeloid leukemia according to the methods provided herein is a middle aged human. In another aspect, the subject treated for acute myeloid leukemia according to the methods provided herein is an elderly human.

In certain aspects, a subject treated for cancer according to the methods provided herein has acute myeloid leukemia that metastasizes to other parts of the body (e.g., bone, lung, and liver). In certain aspects, a subject treated for acute myeloid leukemia according to the methods provided herein is in remission from acute myeloid leukemia. In certain aspects, a subject treated for acute myeloid leukemia according to the methods provided herein presents with a relapse of acute myeloid leukemia. In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is suffering from relapse of one or more symptoms associated with acute myeloid leukemia.

In certain aspects, a subject treated for acute myeloid leukemia according to the methods provided herein is a human of about 1 to 5 years of age, about 5 to 10 years of age, about 10 to 18 years of age, about 18 to 30 years of age, about 25 to 35 years of age, about 35 to 45 years of age, about 40 to 55 years of age, about 50 to 65 years of age, about 60 to 75 years of age, about 70 to 85 years of age, about 80 to 90 years of age, about 90 to 95 years of age, or about 95 to 100 years of age, or any age in between.

In a particular aspect, the subject treated for acute myeloid leukemia according to the methods provided herein is a human being 18 years old or older. In a particular aspect, the subject being treated for acute myeloid leukemia according to the methods provided herein is a human child between the ages of 1and 18. In a certain aspect, a subject treated for acute myeloid leukemia according to the methods provided herein is a human between 12 and 18 years of age. In a certain aspect, the subject is a human male. In another aspect, the subject is a human female. In one aspect, the subject is a human female who is not pregnant or is not lactating. In one aspect, the subject is a female who is pregnant or is about to/likely to be pregnant or is in lactation.

In a particular aspect, the subject being treated for acute myeloid leukemia according to the methods provided herein is a human being in an immunocompromised or immunosuppressed state. In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is a human being undergoing or recovering from immunosuppressive therapy. In certain aspects, a subject treated for acute myeloid leukemia according to the methods provided herein is a human having or at risk for acute myeloid leukemia. In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is a human being that is undergoing, is about to undergo, or has undergone surgery, drug therapy (e.g., chemotherapy), hormone therapy, and/or radiation therapy.

In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is administered compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, or a combination therapy, prior to any adverse effects or intolerance to therapies other than compound 1. In certain aspects, a subject treated for acute myeloid leukemia according to the methods provided herein is a refractory subject. In certain aspects, a refractory subject refers to a subject that is refractory to standard therapy (e.g., surgical therapy, radiation therapy, and/or drug therapy, such as chemotherapy). In certain aspects, a subject with acute myeloid leukemia is refractory when the acute myeloid leukemia is not significantly eradicated and/or one or more symptoms are not significantly alleviated. Using the art-recognized definition of "refractory", a subject is judged whether it is refractory by any method known in the art to analyze the effectiveness of an acute myeloid leukemia treatment in vivo or in vitro.

In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is a human who has proven refractory to therapies other than compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and is no longer receiving such therapies. In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is a human that has received one or more conventional anti-cancer therapies, e.g., surgery, drug therapy (e.g., chemotherapy), anti-androgen therapy, or radiation therapy. These subjects include refractory subjects, subjects that are too young for conventional therapy, and subjects with relapsed acute myeloid leukemia despite treatment with existing therapies.

In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is a human being susceptible to adverse reactions to conventional therapies. In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is a human that has not received treatment (e.g., drug therapy, such as chemotherapy, surgery, anti-androgen therapy, or radiation therapy) prior to administration of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In other aspects, the subject being treated for acute myeloid leukemia according to the methods provided herein is a human that has been treated prior to administration of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In certain aspects, a subject being treated for acute myeloid leukemia according to the methods provided herein is a human that has experienced an adverse effect of a previous treatment or discontinued treatment due to unacceptable levels of toxicity of a previous treatment.

Dosage and administration

According to the method for preventing, treating or ameliorating acute myeloid leukemia provided by the present invention, compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be administered to a subject by various routes in an amount that produces a beneficial or therapeutic effect. According to the method for preventing, treating or ameliorating acute myeloid leukemia provided by the present invention, compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be administered to a subject by oral administration. Oral administration of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof can facilitate compliance with a regimen of taking compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof by a subject in need of such treatment. Thus, in particular aspects, compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered to a subject by oral administration. In another aspect, the subject may or may not have food or water when orally administered compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

Other modes of administration include, but are not limited to, intravenous injection, intradermal injection, intrathecal injection, intramuscular injection, subcutaneous injection, intranasal administration, inhalation, transdermal administration, topical administration, transmucosal administration, intracranial administration, epidural administration, and intrasynovial administration. In one aspect, compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered to a subject in need thereof via a systemic means (e.g., parenterally). In one aspect, compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered (e.g., orally) by allowing compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to cross the blood-brain barrier.

According to the present invention, there is provided a method for preventing, treating or ameliorating acute myeloid leukemia, which comprises administering compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with one or more additional therapies, wherein compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the one or more additional therapies may be administered in the same or different manners.

The method for preventing, treating or ameliorating acute myeloid leukemia provided according to the present invention is effective in administering the dose and administration frequency of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof while minimizing any side effects. The exact dose and frequency of administration of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be determined by a medical practitioner, depending on factors associated with the subject in need of treatment.

Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, responsiveness and tolerance/responsiveness to treatment. The dosage and frequency of administration of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be adjusted over time to provide an effective amount of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof or to maintain a desired effect.

As described herein, a method for preventing, treating or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective amount is a dose administered to the subject twice weekly within different days, wherein the second dose of one week is administered three days after the first dose, wherein the first dose of the following week is administered four days after the second dose of the preceding week.

In a particular aspect, an effective amount is a dose administered to a subject, which may be increased or decreased depending on the subject's response.

In a particular aspect, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective amount is selected from a dose ranging from about 50mg to about 200mg, about 100mg to about 200mg, about 150mg to about 200mg, etc., or any range therebetween, orally twice weekly.

In a particular aspect, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective amount is selected from about 50mg, about 100mg, about 150mg, or about 200mg, etc., or any range therebetween, twice weekly, orally.

In a particular aspect, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the effective amount is about 50mg twice weekly, orally.

In certain aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutical composition thereof, wherein the effective amount is expressed as milligrams per square meter (mg/m)²) The dosage of (a). For example, mg/m of Compound 1²Can be determined by multiplying the animal's conversion factor by the animal dose (in mg/kg) to yield the human dose equivalent in mg/m²And (4) dosage. For regulatory purposes, the following conversion factors may be used: mouse 3, hamster 4.1, rat 6, guinea pig 7.7 (based on Freeich et al, Cancer Chemother. Rep.50(4):219-244(1996)). The height and weight of a human Body can be calculated using the Boyd's Formula of Body Surface Area. In a particular aspect, a method of preventing, treating or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutical composition thereof, wherein the effective amount is between about 0.1mg/m²To about 1000mg/m²Or any range therebetween.

In one aspect, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutical composition thereof, wherein the effective amount is a dose that achieves a target mean plasma concentration of compound 1in a subject with acute myeloid leukemia or a pre-established animal model of acute myeloid leukemia.

In a particular aspect, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutical composition thereof, wherein the effective amount is a dose that achieves the following mean plasma concentrations of compound 1 within 24 hours in a subject with acute myeloid leukemia or a pre-established animal model of acute myeloid leukemia: between about 3hr · μ g/mL to about 70hr · μ g/mL, about 3hr · μ g/mL to about 60hr · μ g/mL, about 3hr · μ g/mL to about 50hr · μ g/mL, about 3hr · μ g/mL to about 40hr · μ g/mL, about 3hr · μ g/mL to about 30hr · μ g/mL, about 3hr · μ g/mL to about 20hr · μ g/mL, about 3hr · μ g/mL to about 10hr · μ g/mL, and the like, or any range therebetween.

In a particular aspect, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutical composition thereof, wherein the effective amount achieves a dose within 24 hours of a subject having acute myeloid leukemia or a pre-established animal model of acute myeloid leukemia of compound 1 as follows: about 3hr · μ g/mL, about 10hr · μ g/mL, about 20hr · μ g/mL, about 30hr · μ g/mL, about 40hr · μ g/mL, about 50hr · μ g/mL, about 60hr · μ g/mL, about 70hr · μ g/mL, and the like, or any range therebetween.

To achieve such plasma concentrations, compound 1 or a pharmaceutical composition thereof may be administered at doses described herein. In certain aspects, subsequent doses of compound 1 or a pharmaceutical composition thereof can be adjusted accordingly based on the mean plasma concentration of compound 1 obtained from administration of compound 1 or a pharmaceutical composition thereof to a subject.

In particular aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutical composition thereof, wherein the effective amount is a dose that achieves a desired ratio of tissue to mean plasma concentration of compound 1 or a pharmaceutical composition thereof in a subject with acute myeloid leukemia or a pre-established animal model of acute myeloid leukemia, e.g., as determined by any imaging technique known in the art.

In certain aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering to the subject an effective amount of compound 1 or a pharmaceutical composition thereof, wherein the effective amount for each dose may or may not be the same. In particular aspects, a first (i.e., initial) dose of compound 1 or a pharmaceutical composition thereof is administered to a subject in need thereof for a first period of time, followed by a second (i.e., additive) dose of compound 1 or a pharmaceutical composition thereof for a second period of time, followed by a third (i.e., maintenance) dose of compound 1 or a pharmaceutical composition thereof for a second period of time. The first dose may be greater than the second dose, or the first dose may be less than the second dose. In a similar manner, the third dose of compound 1 or a pharmaceutical composition thereof can be greater than or less than the second dose, and greater than or less than the first dose.

In certain aspects, the dosage described herein refers to the total amount administered; that is, if more than one compound is administered, the dosage corresponds to the total amount administered. In a particular aspect, the oral composition comprises about 5% to about 95% by weight of compound 1.

According to the methods provided herein for preventing, treating or ameliorating acute myeloid leukemia in a subject in need thereof, the length of time compound 1 or a pharmaceutical composition thereof is administered to the subject in need thereof will be determined by cancer-free survival or symptom-free survival. In certain aspects, the present invention provides methods of treating acute myeloid leukemia comprising administering compound 1 or a pharmaceutical composition thereof for a period of time until the severity and/or number of one or more symptoms associated with acute myeloid leukemia is reduced.

In certain aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering compound 1 or a pharmaceutical composition thereof for up to 48 weeks. In other aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering compound 1 or a pharmaceutical composition thereof for 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 26 weeks (0.5 year), 52 weeks (1 year), 78 weeks (1.5 years), 104 weeks (2 years), or 130 weeks (2.5 years) or more.

In certain aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering compound 1 or a pharmaceutical composition thereof indefinitely. In certain aspects, the present invention provides methods of treating acute myeloid leukemia comprising administering compound 1 or a pharmaceutical composition thereof for a period of time, followed by a period of discontinuation (i.e., no administration of compound 1 or a pharmaceutical composition thereof during the period), and resuming administration of compound 1 or a pharmaceutical composition thereof.

In particular aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering compound 1 or a pharmaceutical composition thereof on a periodic basis, e.g., a 1-week period, a 2-week period, a 3-week period, a 4-week period, a 5-week period, a 6-week period, an 8-week period, a 9-week period, a 10-week period, an 11-week period, or a 12-week period. In such cycles, compound 1 or a pharmaceutical composition thereof may be administered once or twice per week. In particular aspects of the one week cycle, compound 1 or a pharmaceutical composition thereof can be administered twice weekly. In such a particular aspect of the one week cycle, compound 1 or a pharmaceutical composition thereof can be administered once daily.

In particular aspects, the time of administration of compound 1 or a pharmaceutical composition thereof can be determined by one or more monitoring parameters (e.g., the concentration of certain biomarkers).

In particular aspects, the time of administration of compound 1 or a pharmaceutical composition thereof can be adjusted based on one or more monitored parameters (e.g., concentration of the biomarker).

In certain aspects, according to the method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, compound 1 or a pharmaceutical composition thereof is administered to the subject in need thereof before, during, or after a meal (e.g., breakfast, lunch, or dinner). In a specific aspect, according to the methods of the present invention for treating acute myeloid leukemia, compound 1 or the pharmaceutical composition thereof is administered to a subject in need thereof in the morning (e.g., between 5 am and 12 am).

In certain aspects, according to the method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof, compound 1 or a pharmaceutical composition thereof is administered to the subject in need thereof at noon (i.e., 12 pm). In a particular aspect, according to the methods of treating acute myeloid leukemia provided herein, compound 1 or a pharmaceutical composition thereof is administered to a subject in need thereof in the afternoon (e.g., between 12 pm and 5 pm), in the evening (e.g., between 5 pm and bedtime), and/or prior to bedtime.

In particular aspects, an effective amount of compound 1 or a pharmaceutical composition thereof is administered to a subject once daily and twice weekly.

Combination therapy

The present invention provides a combination therapy for the treatment of acute myeloid leukemia, which involves administering compound 1 or a pharmaceutical composition thereof in combination with one or more additional therapies to a subject in need thereof. In a particular aspect, the invention provides a combination therapy for the treatment of acute myeloid leukemia, which involves administering to a subject in need thereof an effective amount of compound 1 or a pharmaceutical composition thereof in combination with an effective amount of another therapy.

In the present invention, the term "in combination with" in the context of administering compound 1 or a pharmaceutical composition thereof, refers to administering compound 1 or a pharmaceutical composition thereof, before, simultaneously with, or after administering one or more additional therapies (e.g., pharmaceutical agents, surgery, or radiation) for the treatment of acute myeloid leukemia. The use of the term "in combination" does not limit the order in which one or more therapeutic agents and one or more additional therapies are administered to a subject. In particular aspects, the time interval between administration of compound 1 or a pharmaceutical composition thereof and administration of one or more additional therapies can be about 1-5 minutes, 1-30 minutes, 30 minutes to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 26 weeks, 52 weeks, 11-15 weeks, 15-20 weeks, 20-30 weeks, 30-40 weeks, 40-50 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or any time period in between. In certain aspects, the dosing interval between compound 1 or a pharmaceutical composition thereof and one or more additional therapies is less than 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years.

In certain aspects, the combination therapies provided herein involve administering compound 1 or a pharmaceutical composition thereof daily and one or more additional therapies weekly, biweekly, every four weeks, monthly, every two months (e.g., about 8 weeks), every three months (e.g., about 12 weeks), or every four months (e.g., about 16 weeks). In certain aspects, compound 1 or a pharmaceutical composition thereof and one or more additional therapies are cyclically administered to a subject. Cycling therapy involves administering compound 1 or a pharmaceutical composition thereof for a period of time, followed by one or more additional therapies for a period of time, and repeating the sequential administration. In certain aspects, the cycling therapy can further comprise discontinuing the drug for a period of time, wherein compound 1 or the pharmaceutical composition thereof, or the adjunct therapy, is not administered for a period of time (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 20 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, or 3 years). In one aspect, the number of cycles of administration is 1 to 12 cycles, 2 to 10 cycles, or 2 to 8 cycles.

In certain aspects, a method of preventing, treating, or ameliorating acute myeloid leukemia in a subject in need thereof comprises administering compound 1 or a pharmaceutical composition thereof as a single agent for a period of time prior to administering compound 1 or a pharmaceutical composition thereof in combination with an additional therapy. In certain aspects, the present invention provides methods of treating acute myeloid leukemia comprising administering the additional therapy alone for a period of time prior to administering compound 1 or a pharmaceutical composition thereof and the additional therapy.

In certain aspects, administration of compound 1 or a pharmaceutical composition thereof in combination with one or more additional therapies according to the methods provided herein has an additive effect relative to administration of compound 1 or a pharmaceutical composition thereof or one or more additional therapies alone. In certain aspects, administration of compound 1 or a pharmaceutical composition thereof in combination with one or more additional therapies according to the methods provided herein has a synergistic effect relative to administration of compound 1 or a pharmaceutical composition thereof or one or more additional therapies alone.

In the present invention, the term "synergistic" refers to the effect of administering compound 1 or a pharmaceutical composition thereof in combination with one or more additional therapies (e.g., agents) that is more effective than the additive effects of any two or more monotherapies (e.g., agents).

In particular aspects, the synergistic effect of the combination therapy allows for the use of a lower dose (i.e., a sub-optimal dose) of compound 1 or a pharmaceutical composition thereof or an additional therapy, and/or less frequent administration of compound 1 or a pharmaceutical composition thereof or an additional therapy to a subject.

In certain aspects, the use of a lower dose of compound 1 or a pharmaceutical composition thereof or adjunctive therapy, and/or less frequent administration of compound 1 or a pharmaceutical composition thereof or adjunctive therapy, without reducing the efficacy of compound 1 or a pharmaceutical composition thereof or adjunctive therapy, respectively, in the treatment of acute myeloid leukemia can reduce toxicity associated with the administration of compound 1 or a pharmaceutical composition thereof or adjunctive therapy, respectively.

In certain aspects, the synergistic effect results in an increased efficacy of compound 1 or the pharmaceutical composition thereof, or each of said adjunctive therapies in the treatment of acute myeloid leukemia. In certain aspects, the synergistic effect of compound 1 or a pharmaceutical composition thereof used in combination with one or more additional therapies reduces the adverse or harmful side effects associated with the use of any single therapy.

A combination of compound 1 or a pharmaceutical composition thereof and one or more additional therapies can be administered to a subject in the same pharmaceutical composition. Alternatively, compound 1 or a pharmaceutical composition thereof and one or more additional therapies may be administered to the subject simultaneously in separate pharmaceutical compositions. Compound 1 or a pharmaceutical composition thereof and one or more additional therapies may be administered to a subject sequentially in separate pharmaceutical compositions. Compound 1 or a pharmaceutical composition thereof and one or more additional therapies can also be administered to a subject by the same or different routes of administration.

The combination therapy provided herein involves administering compound 1 or a pharmaceutical composition thereof to a subject in need thereof in combination with conventional or known therapies for treating acute myeloid leukemia. Other therapies for acute myeloid leukemia or conditions related thereto aim to control or alleviate one or more symptoms. Thus, in certain aspects, the combination therapies provided herein involve administering an analgesic, or other therapy directed at alleviating or controlling one or more symptoms associated with or a condition associated with acute myeloid leukemia, to a subject in need thereof.

Specific examples of anticancer agents that can be used in combination with compound 1 or a pharmaceutical composition thereof for the treatment of acute myeloid leukemia include: hormonal agents (e.g., aromatase inhibitors, Selective Estrogen Receptor Modulators (SERMs) and estrogen receptor antagonists), chemotherapeutic agents (e.g., microtubule depolymerization blockers, antimetabolites, topoisomerase inhibitors and DNA cross-linking or damaging agents), anti-angiogenic agents (e.g., VEGF antagonists, receptor antagonists, integrin antagonists, Vascular Targeting Agents (VTAs)/Vascular Disrupting Agents (VDAs), radiation therapy and general surgery.

Non-limiting examples of hormonal agents that may be used in combination with compound 1 or a pharmaceutical composition thereof for the treatment of acute myeloid leukemia include aromatase inhibitors, SERMs and estrogen receptor antagonists. Hormonal agents as aromatase inhibitors may be steroids or non-steroids. Non-limiting examples of non-steroidal hormonal agents include letrozole, anastrozole, aminoglutethimide, fadrozole, and vorozole. Non-limiting examples of steroid hormone agents include anoxin (exemestane), formestane, and testosterone lactone. Non-limiting examples of hormonal agents as SERM include tamoxifen (trade mark/sold as) Afifene, azoxifene, bazedoxifene, clomiphene, Futenoxicam, lasofoxifene, Oximexifene, Raloxifene, and toremifene. Non-limiting examples of hormonal agents that are estrogen receptor antagonists include fulvestrant. Other hormonal agents include, but are not limited to, abiraterone and lonapone.

Non-limiting examples of chemotherapeutic agents that can be used in combination with compound 1 or a pharmaceutical composition thereof to treat cancer include microtubule depolymerization blockers, antimetabolites, topoisomerase inhibitors, and DNA cross-linking or damaging agents.

Chemotherapeutic agents that act as microtubule depolymerization blockers include, but are not limited to, the taxoids (e.g., paclitaxel (trade mark/sale: paclitaxel)) Docetaxel, an albumin-bound paclitaxel (nabPaclitaxel, trade mark/sale is) Larotaxel, ortataxel and tesetaxel (tesetaxel)); epothilones (e.g., ixabepilone); and vinca alkaloids (e.g., vinorelbine, vinblastine, vindesine and vincristine (trade mark/sale is))。

Chemotherapeutic agents that are antimetabolites include, but are not limited to, folate antimetabolites (e.g., methotrexate, aminopterin, pemetrexed, raltitrexed); purine antimetabolites (e.g., cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine); pyrimidine antimetabolites (e.g., 5-fluorouracil, capecitabine, gemcitabine)Cytarabine, decitabine, floxuridine, tegafur); and deoxyribonucleotide antimetabolites (e.g., hydroxyurea).

Chemotherapeutic agents that are topoisomerase inhibitors include, but are not limited to, class I (camptothecin) topoisomerase inhibitors (e.g., topotecan (trade mark/sold as) Irinotecan, rubitecan and belotecan); class II (Podophyllum) topoisomerase inhibitors (e.g., etoposide or VP-16 and teniposide); anthracyclines (e.g., doxorubicin, epirubicin, doxorubicin hydrochloride liposome, aclarubicin, amrubicin, daunorubicin, idarubicin, pirarubicin, valrubicin, and zorubicin); and anthracenediones (e.g., mitoxantrone and pixantrone).

Chemotherapeutic agents that act as DNA crosslinking agents (or DNA damaging agents) include, but are not limited to, alkylating agents (e.g., cyclophosphamide, dichloromethyldiethylamine, ifosfamide (trade mark/sale: Tokyo)) Trilobine, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine (trade mark/sale as) Lomustine, semustine, fotemustine, nimustine, ranimustine, streptozotocin, busulfan, mannosuman, trooshusuon, carboquinone, N' -triethylenethiophosphoramide, triaminoquinone, tritamin); alkylating-like agents (e.g., carboplatin (trade mark/sale as)) Cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, satraplatin, picoplatin); non-classical DNA cross-linking agents (e.g. procarbazine, dacarbazine, temozolomide (trade mark/sale) Hexamethylmelamine, dibromomannitol); and intercalators (e.g., actinomycin, bleomycin, mitomycin and plicamycin).

Non-limiting examples of anti-angiogenic agents that can be used in combination with compound 1 or a pharmaceutical composition thereof to treat acute myeloid leukemia include VEGF antagonists, receptor antagonists, integrin antagonists (e.g., Vitaxin, cilengitide, and S247) and VTAs/VDAs (e.g., fosbretylabulin). VEGF antagonists include, but are not limited to, anti-VEGF antibodies (e.g., bevacizumab (trade Mark/sale as)) And ranibizumab (trade mark/sale as) VEGF fusion protein (VEGF trap) (e.g., aflibercept), antisense VEGF gene (VEGF antisense) or siRNA or miRNA and aptamer (e.g., pegaptanib sodium (trade mark/sale as)). Anti-angiogenic agents that are receptor antagonists include, but are not limited to, antibodies (e.g., ramucirumab) and kinase inhibitors (e.g., sunitinib, sorafenib, cediranib, pazopanib, vandetanib, axitinib, and AG-013958), such as tyrosine kinase inhibitors. Other non-limiting examples of anti-angiogenic agents include ATN-224, anecortave acetate (trade mark/sale) Microtubule depolymerization inhibitors (e.g., combretastatin a4 prodrug), proteins or protein fragments (e.g., collagen 18 (endostatin)).

Non-limiting examples of other therapies that can be administered to a subject in combination with compound 1 or a pharmaceutical composition thereof to treat acute myeloid leukemia include:

(1) statins, e.g. lovastatin (e.g. trade mark/sale of)；

(2) mTOR inhibitors, such as sirolimus, also known as rapamycin (e.g., trademarks/sales as) Temsirolimus (e.g., trade mark/sale as) Sirolimus (e.g., trade mark/sale as) And 42- (dimethylphosphineoyl) rapamycin (Deforolimus);

(3) farnesyl transferase inhibitors, e.g. tipifarnib (e.g. trade mark/sale of)；

(4) Anti-fibrotic agents, such as pirfenidone;

(5) pegylated interferons, such as PEG interferon alpha-2 b;

(6) CNS stimulants, e.g. methylphenidate (trade mark/sale)；

(7) HER-2 antagonists, such as anti-HER-2 antibodies (e.g., trastuzumab) and kinase inhibitors (e.g., lapatinib);

(8) IGF-1 antagonists, such as anti-IGF-1 antibodies (e.g., AVE1642 and IMC-A11) or IGF-1 kinase inhibitors;

(9) EGFR/HER-1 antagonists, such as anti-EGFR antibodies (e.g., cetuximab, panitumumab) or EGFR kinase inhibitors (e.g., erlotinib (e.g., trade mark/sale as) Gefitinib);

(10) SRC antagonists, such as bosutinib;

(11) cyclin Dependent Kinase (CDK) inhibitors, such as celecoxib;

(12) janus kinase 2 inhibitors, such as lestaurtinib;

(13) proteasome inhibitors, such as bortezomib;

(14) phosphodiesterase inhibitors, such as anagrelide;

(15) inosine monophosphate dehydrogenase inhibitors such as thiazolfurin;

(16) lipoxygenase inhibitors, such as maxorol;

(17) an endothelin antagonist;

(18) retinoid receptor antagonists, such as tretinoin or alitretinoin;

(19) immunomodulators, such as lenalidomide, pomalidomide or thalidomide (e.g. trade mark/sale of)；

(20) Kinases (e.g. kinases)Tyrosine kinase) inhibitors, such as imatinib (e.g., trade mark/sale of) Dasatinib, erlotinib, nilotinib, gefitinib, sorafenib, sunitinib (e.g., tradename/sale of) Lapatinib, AEE788, or TG 100801;

(21) non-steroidal anti-inflammatory drugs, e.g. celecoxib (trade mark/sale as)；

(22) Human granulocyte colony-stimulating factor (G-CSF), e.g. filgrastim (trade mark/sale as)

(23) Folinic acid or calcium folinate;

(24) integrin antagonists, such as integrin α 5 β 1-antagonists (e.g., JSM 6427);

(25) nuclear factor kappa beta (NF-k beta) antagonists, such as OT-551, which are also an antioxidant;

(26) hedgehog inhibitors, such as CUR61414, cyclopamine, GDC-0449 or anti-hedgehog antibodies;

(27) histone Deacetylase (HDAC) inhibitors, such as SAHA (also known as vorinostat (trade mark/sale: vox)PCI-24781, SB939, CHR-3996, CRA-024781, ITF2357, JNJ-26481585, or PCI-24781;

(28) retinoids, e.g. isotretinoin (e.g. trade mark/sale as)；

(29) Hepatocyte growth factor/scatter factor (HGF/SF) antagonists, such as HGF/SF monoclonal antibodies (e.g., AMG 102);

(30) synthetic chemicals, such as antineoplastic drugs;

(31) antidiabetic agents, such as rosiglitazone maleate (e.g., trade mark/sale as)；

(32) Antimalarial and amebiase, e.g. chloroquine (e.g. trade mark/sale as)；

(33) Synthetic bradykinin, such as RMP-7;

(34) platelet derived growth factor receptor inhibitors, such as SU-101;

(35) Flk-1/KDR/VEGFR2, FGFR 1and PDGFR β receptor tyrosine kinase inhibitors such as SU5416 and SU 6668;

(36) anti-inflammatory agents, such as sulfasalazine (e.g., trade mark/sale as) (ii) a And

(37) TGF-beta antisense therapy.

Non-limiting examples of other therapies that can be administered to a subject in combination with compound 1 or a pharmaceutical composition thereof to treat acute myeloid leukemia include: synthetic nonapeptide analogues of naturally occurring gonadotropin releasing hormone, e.g. leuprolide acetate (trade mark/sale) (ii) a Non-steroidal antiandrogens, e.g. flutamide (trade mark/sale) Or nilutamide (trade mark/sale is) (ii) a Non-steroidal androgen receptor inhibitorsFormulations, e.g. bicalutamide (trade mark/sale(ii) a Steroid hormones, such as progesterone; antifungal agents, e.g. ketoconazole (trade mark/sale) (ii) a Glucocorticoids, such as prednisone; estramustine sodium phosphate (trade mark/sale as) (ii) a And bisphosphonates, such as pamidronate, alendronate and risedronate.

Other specific examples of therapies that can be used in combination with compound 1 or a pharmaceutical composition thereof to treat acute myeloid leukemia include, but are not limited to, agents associated with cancer immunotherapy (e.g., cytokines, interleukins, and cancer vaccines).

Specific examples of agents that may be used in combination with compound 1 or a pharmaceutical composition thereof for alleviating the side effects associated with acute myeloid leukemia include, but are not limited to: antiemetic agents, e.g. ondansetron hydrochloride (trade mark/sale of) Granisetron hydrochloride (trade mark/sale as) Lorazepam (trade mark/sale is) Dexamethasone (trade mark/sale)。

In certain aspects, the combination therapies provided herein for the treatment of acute myeloid leukemia comprise administering compound 1 or a pharmaceutical composition thereof in combination with one or more agents for the treatment and/or management of side effects; side effects are for example: bleeding (usually temporary, low-grade epistaxis), arterial and venous embolism, hypertension, delayed wound healing, asymptomatic urine protein, perforation of the nasal septum, reversible back leukoencephalopathy syndromes associated with hypertension, dizziness, dyskinesia, headache, hoarseness, nausea, vomiting, diarrhea, rash, subungual bleeding, myelodysplastic syndromes, myelosuppression, fatigue, hypothyroidism, prolongation of the QT interval or heart failure.

In certain aspects, compound 1 or a pharmaceutical composition thereof is not combined with a drug primarily metabolized by CYP2D6 in the treatment of acute myeloid leukemia; drugs metabolized by CYP2D6 are for example: antidepressants (e.g., tricyclic antidepressants, selective 5-hydroxytryptamine reuptake inhibitors, etc.), antipsychotics, beta-adrenoceptor blockers, or certain antiarrhythmic types of drugs.

Reagent kit

The present invention provides a pharmaceutical package or kit comprising one or more containers filled with compound 1 or a pharmaceutical composition thereof. In addition, the pharmaceutical package or kit may also include one or more other therapies or other related agents useful for treating acute myeloid leukemia. The present invention also provides a pharmaceutical package or kit comprising one or more containers filled with one or more components of the pharmaceutical composition of the invention.

Optionally associated with such a kit is a notice form for the production, use or sale of a pharmaceutical or biological product as mandated by a governmental agency, which notice reflects approval by the agency for human administration.

The invention will be further understood by reference to the following non-limiting specific examples.

Examples

Example 1

The P31-Fujioka cell line was injected into immunodeficient mice (NRG-SGM 3). Implantation of P31 cells in mice was confirmed by flow cytometry detection of the human CD45 marker 10 days after injection (data not shown). One group of mice was orally administered compound 1, and the other group of mice, age matched to the graft, was administered vehicle control. Results are shown in figure 1, survival curves for compound 1and vehicle-treated mice (n-5 mice per group, P < 0.002). The results show that compound 1 can significantly delay the incubation period of the disease in mice compared to the control group.

Example 2

Human MOLT-4-AML cells were injected Intravenously (IV) into male Non-Obese Diabetic (NON-Obese diabetes, NOD) Severe Combined Immunodeficiency (SCID) mice, based on which an Acute Myelogenous Leukemia (AML) mouse model was established for the following studies. MOLT-4 cells were CD3 positive, and NOD-SCID mice were derived from Jackson Laboratory, Bar Harbor, Maine (Jackson Laboratory, Bar Harbor Maine).

Human AML tumor cells were treated with MOLM13 from ATCC (5X 10 in 200. mu.L PBS)⁶Individual cells) were inoculated into male NOD-SCID mice, each mouse was injected intravenously with 0.2 mL. Three days after tumor inoculation, mice were randomized into 4 groups of 5 mice each, each group administered once daily according to the following schedule: (group 1) oral vehicle (0.5% HPMC), (group 2) oral compound 1in HPMC solution (12.5mg/kg), (group 3) oral compound 2 in HPMC solution (10mg/kg), (group 4) oral compound 1in HPMC solution (12.5mg/kg) and compound 2 in HPMC solution (10mg/kg) in combination for 75 days.

The results of the study are shown in figures 2 to 5, figure 2 shows the percent change in body weight of group 1and group 2 (vehicle vs compound 1) after 75 days of treatment, while figure 3 shows the survival curves of group 1and group 2 mice. The results show that the lifespan of mice administered compound 1 is significantly extended compared to mice administered vehicle. Figure 4 shows the percent change in body weight of all four groups of mice studied, while figure 5 shows the survival curves of all four groups of mice. Mice administered compound 1 alone or compound 1in combination with compound 2 survived significantly longer than mice administered compound 2 alone.

Example 3

MOLT human Acute Lymphoid Leukemia (ALL) tumor cells from ATCC (1X 10 in 200. mu.L PBS)⁷Individual cell) Male NOD-SCID mice were inoculated, and each mouse was injected intravenously with 0.2 mL. 7 days after tumor inoculation, mice were randomized into 7 groups of 5 mice each, and each group was dosed according to the following schedule: (group 1) daily oral vehicle (0.5% HPMC and 0.1% Tween 80), (group 2) Compound 1(10mg/kg) was administered orally twice weekly, (group 3) Compound 2(10mg/kg) was administered orally daily, (group 4) Adriamycin (1mg/kg) was injected Intraperitoneally (IP) once weekly, (group 5) Adriamycin (0.5mg/kg) was injected by IP once weekly, (group 6) Ara-C (50mg/kg) was injected by IP twice weekly, (group 7) Ara-C (70mg/kg) was injected by IP once weekly.

The results of the survival curves for the 7 groups of mice in this study are shown in figure 6. As can be seen in fig. 6, the maximum survival days for each group of mice are as follows: group 1 (vehicle) 70 days, group 2 (compound 1)65 days, group 3 (compound 2)160 days, group 4 (doxorubicin 1.0qw)40 days, group 5 (doxorubicin 0.5qw)40 days, group 6 (Ara-C50 biw)65 days, group 7 (Ara-C70 qw)70 days.

All documents cited in this specification are incorporated herein by reference in their entirety into this application to the same extent as if each individual reference were specifically and individually indicated to be incorporated by reference herein for all and all purposes.

Having now fully described the subject matter of the claims, it will be understood by those of ordinary skill in the art that the subject matter of the claims can be carried out within a wide range of equivalents without affecting the scope of the subject matter or aspects described herein. It is intended that the following claims be interpreted to include all such equivalents.

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Method for treating acute myeloid leukemia

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