Macrocyclic compounds and uses thereof
阅读说明：本技术 大环化合物及其用途 (Macrocyclic compounds and uses thereof ) 是由 Y.岸 吉良和信 伊藤宪 于 2018-04-03 设计创作，主要内容包括：本发明提供具有肿瘤血管重塑效应和/或抗CAF(癌症相关成纤维细胞)活性的新颖化合物(1)或其药学上可接受的盐,其任选在药学上可接受的载体中；及其医学用途。<Image he="345" wi="700" file="DDA0002278953540000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides novel compounds (1) or a pharmaceutically acceptable salt thereof, having a tumor vascular remodeling effect and/or anti-CAF (cancer associated fibroblast) activity, optionally in a pharmaceutically acceptable carrier; and medical uses thereof.)
1. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in inhibiting the growth of a tumor or cancer characterized by angiogenesis, invasion or metastasis.
4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumour or cancer characterised by angiogenesis, invasion or metastasis.
5. The compound for use according to claim 3 or 4, wherein the cancer or tumour is a head and neck cancer, breast cancer, oesophageal cancer, uterine cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, small bowel cancer, bladder cancer or sarcoma.
6. The compound for use according to claim 5, wherein the cancer or tumor is a head and neck cancer.
7. The compound for use according to claim 6, wherein the cancer or tumor is squamous cell carcinoma of the head and neck (SCCHN).
8. The compound for use according to claim 6, wherein the cancer is adenoid cystic carcinoma.
9. The compound for use according to claim 5, wherein the cancer or tumor is breast cancer.
10. The compound for use according to claim 9, wherein the cancer or tumor is HER2 positive breast cancer.
11. The compound for use according to claim 9, wherein the cancer or tumor is HER2 negative breast cancer.
12. The compound for use according to claim 9, wherein the cancer or tumor is triple negative breast cancer.
13. The compound for use according to claim 5, wherein the cancer or tumor is colorectal cancer.
14. The compound for use according to claim 5, wherein the cancer or tumor is esophageal cancer.
15. The compound for use according to claim 14, wherein the cancer or tumor is esophageal adenocarcinoma.
16. The compound for use according to claim 5, wherein the cancer or tumor is uterine cancer.
17. The compound for use according to claim 5, wherein the cancer or tumor is ovarian cancer.
18. The compound for use according to claim 5, wherein the cancer or tumor is a sarcoma.
19. The compound for use according to claim 18, wherein the cancer or tumor is uterine sarcoma, fibrosarcoma, synovial sarcoma, soft tissue sarcoma or angiosarcoma.
20. The compound for use according to claim 5, wherein the cancer or tumor is gastric cancer.
21. The compound for use according to claim 5, wherein the cancer or tumor is small bowel cancer.
22. The compound for use according to claim 21, wherein the cancer or tumor is small intestine adenocarcinoma.
23. The compound for use according to claim 5, wherein the cancer or tumor is bladder cancer.
24. The compound for use according to claim 5, wherein the cancer or tumor is a urothelial cancer.
25. The compound for use according to any one of claims 4 to 24, for use in combination with a programmed death 1 protein (PD-1) antibody.
26. The compound for use according to any one of claims 4 to 24, for use in combination with a programmed death L1 protein (PD-L1) antibody.
27. The compound for use according to any one of claims 4 to 24, for use in combination with an anti-EGFR (epidermal growth factor receptor) antibody.
28. The compound for use of claim 27, wherein the anti-EGFR antibody is an anti-EGFR mAb.
29. The compound for use according to claim 27 or 28, wherein the cancer or tumor is a head and neck cancer.
30. The compound for use according to claim 29, wherein the cancer or tumor is squamous cell carcinoma of the head and neck (SCCHN).
31. The compound for use according to any one of claims 28 to 30, wherein the anti-EGFR mAb is cetuximab.
32. The compound for use according to any one of claims 4 to 24, for use in combination with a HER2 (human epidermal growth factor receptor) antibody.
33. The compound for use of claim 32, wherein the HER2 antibody is HER2 mAb.
34. The compound for use according to claim 32 or 33, wherein the cancer is breast cancer.
35. The compound for use of claim 33 or 34, wherein the HER2mAb is trastuzumab.
36. A compound for use according to any one of claims 4 to 24, for use in combination with radiotherapy.
37. A compound for use according to any one of claims 4 to 24, for use in combination with surgery.
38. A method of treating a tumor or cancer characterized by angiogenesis, invasion, or metastasis in a subject, comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
39. The method of claim 38, wherein the cancer or tumor is a head and neck cancer, breast cancer, esophageal cancer, uterine cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, small bowel cancer, bladder cancer, or sarcoma.
40. The method of claim 39, wherein the cancer or tumor is a head and neck cancer.
41. The method of claim 40, wherein the cancer or tumor is squamous cell carcinoma of the head and neck (SCCHN).
42. The method of claim 40, wherein the cancer is adenoid cystic carcinoma.
43. The method of claim 39, wherein the cancer or tumor is breast cancer.
44. The method of claim 43, wherein the cancer or tumor is HER2 positive breast cancer.
45. The method of claim 43, wherein the cancer or tumor is HER2 negative breast cancer.
46. The method of claim 43, wherein the cancer or tumor is triple negative breast cancer.
47. The method of claim 39, wherein the cancer or tumor is colorectal cancer.
48. The method of claim 39, wherein the cancer or tumor is esophageal cancer.
49. The method of claim 48, wherein the cancer or tumor is esophageal adenocarcinoma.
50. The method of claim 39, wherein the cancer or tumor is uterine cancer.
51. The method of claim 39, wherein the cancer or tumor is ovarian cancer.
52. The method of claim 39, wherein the cancer or tumor is a sarcoma.
53. The method of claim 52, wherein the cancer or tumor is uterine sarcoma, fibrosarcoma, synovial sarcoma, soft tissue sarcoma, or angiosarcoma.
54. The method of claim 39, wherein the cancer or tumor is gastric cancer.
55. The method of claim 39, wherein the cancer or tumor is small bowel cancer.
56. The method of claim 55, wherein the cancer or tumor is small bowel adenocarcinoma.
57. The method of claim 39, wherein the cancer or tumor is bladder cancer.
58. The method of claim 39, wherein the cancer or tumor is a urothelial cancer.
59. The method of any one of claims 39 to 58, comprising further treating the subject with a programmed death 1 protein (PD-1) antibody.
60. The method of any one of claims 39 to 58, comprising further treating the subject with a programmed death L1 protein (PD-L1) antibody.
61. The method of any one of claims 39 to 58, comprising further treating the subject with an anti-EGFR (epidermal growth factor receptor) antibody.
62. The method of claim 61, wherein the anti-EGFR antibody is an anti-EGFR mAb.
63. The method of claim 61 or 62, wherein the cancer or tumor is a head and neck cancer.
64. The method of claim 63, wherein the cancer or tumor is squamous cell carcinoma of the head and neck (SCCHN).
65. The method of any one of claims 62 to 64, wherein the anti-EGFR mAb is cetuximab.
66. The method of any one of claims 39 to 58, comprising further treating the subject with a HER2 (human epidermal growth factor receptor) antibody.
67. The method of claim 66, wherein the HER2 antibody is HER2 mAb.
68. The method of claim 66 or 67, wherein the cancer is breast cancer.
69. The method of claim 67 or 68, wherein the HER2mAb is trastuzumab.
70. A method of treating HER2 negative breast cancer or Squamous Cell Carcinoma of Head and Neck (SCCHN) in a subject comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
71. The method of any one of claims 39 to 70, comprising further treating the subject with radiation therapy.
72. The method of any one of claims 39 to 71, comprising further treating the subject with surgery.
73. The method of any one of claims 39 to 72, wherein the subject is a human.
74. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the growth of a tumor or cancer characterized by angiogenesis, invasion or metastasis.
75. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a tumor or cancer characterized by angiogenesis, invasion or metastasis.
Technical Field
The present invention provides novel macrocyclic compounds having a tumor vascular remodeling effect and anti-CAF (cancer-associated fibroblast) activity. The compounds are useful for treating cancer or inhibiting tumor growth in a subject.
Prior Art
Halichondrins (Halichondrins), such as Halichondrin B, are anti-cancer agents that were originally isolated from Marine Sponge black soft Sponge (Halichondria okadai) (see, e.g., d.uemura et al, "Norhalichondrin a: An anti inflammatory macromolecular Marine Sponge from Marine Sponge" j.am. chem. soc. 107,4796(1985)), and were subsequently found in axacumella (Axinella sp.), brown oblatum Sponge (Phakellia carteri), and flat Sponge (lisondendix sp.) Total Synthesis of Halichondrin B was published in 1992 (see, e.g., y.kishi et al, "Total Synthesis of Halichondrin B and Norhalichondrin B" j.chem.chem.62, 1992, "for example, Halichondrin B and hypotubulin binding to microtubule proteins, such as in vitro binding proteins, see, e.g., protein 31, cathelicidin B, and the like," microtubule protein binding to microtubule proteins ", see, e.g. 9,3, 1985, and" microtubulin binding proteins to human microtubulin in vitro "(see, e.g. 9, 3.9, 3, and" microtubulin binding proteins ".
Eribulin mesylate, Halaven, developed based on halichondrin BTM) (see, for example, International publication No. WO 1999/065894 published on 23/12 1999; international publication No. WO 2005/118565, published at 12/15/2005; and W.ZHENG et al, "multicyclic ketone analogues of halichondrin B" Bioorganic medical Chemistry Letters 14,5551-5554(2004)) are currently in clinical use in many countries for the treatment of, for example, metastatic breast cancer and advanced liposarcoma.
Other patent publications describing halichondrin include U.S. patent No. 5,436,238 issued to Kishi et al on 25/7/1995; U.S. patent No. 5,338,865 to Kishi et al, 8, 16, 1994; and WO 2016/003975 filed by Kishi et al, all assigned to the President and Fellows of Harvard College (President and Fellows of Harvard College).
See also, for example, U.S. patent nos. 5,786,492; U.S. patent No. 8,598,373; U.S. patent No. 9,206,194; U.S. patent No. 9,469,651; WO/2009/124237A 1; WO/1993/017690A 1; WO/2012/147900A 1; U.S. patent No. 7,982,060; U.S. patent No. 8,618,313; U.S. patent No. 9,303,050; U.S. patent No. 8,093,410; U.S. patent No. 8,350,067; U.S. patent No. 8,975,422; U.S. patent No. 8,987,479; U.S. patent No. 8,203,010; U.S. patent No. 8,445,701; U.S. patent No. 8,884,031; U.S. Pat. nos. RE45,324; U.S. patent No. 8,927,597; U.S. patent No. 9,382,262; U.S. patent No. 9,303,039; WO/2009/046308A 1; WO/2006/076100A 3; WO/2006/076100A 2; WO/2015/085193A 1; WO/2016/176560A 1; U.S. patent No. 9,278,979; U.S. patent No. 9,029,573; WO/2011/094339A 1; WO/2016/179607A 1; WO/2009/064029A 1; WO/2013/142999A 1; WO/2015/066729A 1; WO/2016/038624A 1; and WO/2015/000070A 1.
Cancer-associated fibroblasts (CAF), which are widely found in a variety of solid tumors, are stromal cells. CAF is known to play an important role in angiogenesis, invasion and metastasis. It has been reported that there is a close correlation between the amount of CAF and the clinical prognosis in, for example, invasive Breast Cancer (see, e.g., M.Yamashita et al, "Role of linear stains in invasive cleavage Cancer. linear expressions of alpha-smooth tissue with a fibrous outer group" Breast Cancer 19,170,2012) and esophageal adenocarcinoma (see, e.g., T.J.Underwood et al, "Cancer-assisted stains present either pore group and proteopeptivity invasion in invasive adsorption Cancer" Journal of Patholol. 235,466,2015). CAF has also been reported to be associated with various tumors such as breast cancer (see, e.g., p. farmer et al, "a strain-related gene signature in breast cancer" Nature medicine, 15(1),68,2009) and head and neck cancer (see, e.g., s.schmitz et al, "center protein epitope to dominant diagnosis and cancer associated with tumor in tissue with head and neck cancer" oncogene, 6(33), (34288,2015; y. matsuoka et al, "The tissue strain associated with tumor with therapy to 5-FU-weighted polypeptide vaccine and tissue cancer) 205,2015. fig.3.
It has thus been observed that the effects of tumor vascular remodeling and anti-CAF activity lead to an improvement in the cancer microenvironment, which contributes to tumor therapy. Blood vessels are essential for the growth of tumors. In addition to reducing hypoxia, the reconstituted blood vessels in the tumor can also deliver anti-cancer agents to the tumor. It is reported that the erebral-induced abnormal tumor vasculature remodeling produces a more functional microenvironment that can reduce tumor invasiveness by eliminating internal tumor hypoxia. The ability of erebral to significantly reverse these invasive features may contribute to its clinical benefit due to both enhanced resistance and metastasis of abnormal tumor microenvironments (see, e.g., y. funahashi et al, "experimental tissue recovery process molecular biology modification in clinical human breast cancer models" cancer sci.105(2014), 1334-. To date, no anticancer drugs having a tumor vascular remodeling effect and anti-CAF activity have been reported.
Despite advances, there remains a need for additional compounds to facilitate the study and medical care of tumors and cancers.
Disclosure of Invention
The present invention relates to a macrocyclic compound having a tumor vascular remodeling effect and anti-CAF activity (e.g., compound (1)), and pharmaceutically acceptable salts thereof and isotopically labeled derivatives thereof, and pharmaceutical compositions thereof.
The invention also includes methods of treating cancer, methods of reversibly or irreversibly inhibiting cellular mitosis, and methods of inhibiting tumor growth in vitro, in vivo, or in a subject using compound (1). In another aspect, the present invention provides a kit comprising compound (1) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
In one aspect, the invention features a compound that is compound (1):
and pharmaceutically acceptable salts thereof; and isotopically labeled derivatives thereof.
In one aspect, the present invention provides a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof. The pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical composition may further comprise one or more additional therapeutic agents in the form of combination, alternation, or other kinds of concurrent therapy to achieve the desired goal of treatment.
The present invention also features a method of preparing the compound (1) or an intermediate thereof. Synthetic intermediates are also provided herein as part of the invention.
It has been found that compound (1) has a beneficial effect on tumor vascular remodeling and has anti-CAF activity, as shown in the figures and examples. Thus, compound (1) has potential use in the treatment of cancer, such as squamous cell carcinoma of the head and neck (SCCHN), breast cancer, esophageal cancer, uterine cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, small bowel cancer, bladder cancer, sarcoma, rare cancers.
In another aspect, the present invention provides a method of inhibiting any tumor growth or cancer in a subject (typically a human) that is responsive to a compound having a tumor vascular remodeling effect and/or anti-CAF activity, using compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof.
Compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a composition thereof, can be administered in combination with any other active agent that provides a beneficial result to the patient. In certain embodiments, compound (1) is used in combination with an antibody (e.g., a monoclonal antibody). In one embodiment, compound (1) is used in combination, alternation, or other concurrent therapy with an immunotherapy, such as an anti-EGFR (epidermal growth factor receptor) antibody, an anti-HER 2 (human epidermal growth factor receptor) antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody, as set forth in more detail below.
For example, there is provided a method of treating Squamous Cell Carcinoma of Head and Neck (SCCHN) in a subject, typically a human, in need thereof, comprising administering to the subject an effective amount of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or composition thereof in combination with an anti-EGFR (epidermal growth factor receptor) monoclonal antibody (mAb) therapy. In certain embodiments, the anti-EGFR (epidermal growth factor receptor) mAb is cetuximab (cetuximab).
As another example, there is provided a method of treating breast cancer in a subject (typically a human) in need thereof, comprising administering to the subject an effective amount of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a composition thereof in combination with HER2 (human epidermal growth factor receptor) mAb therapy. In certain embodiments, the HER2 (human epidermal growth factor receptor) mAb is trastuzumab (trastuzumab). In other embodiments, compound (1) may be used in combination with traditional chemotherapy (e.g., doxorubicin (adriamycin), cyclophosphamide, paclitaxel, etc.) or antiestrogens (e.g., selective estrogen modulators (SERMs), selective estrogen degraders (SERDs), partial or complete estrogen inhibitors (e.g., fulvestrant)) or
Another aspect of the present invention provides compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, in a kit (which can be in the form of a dosage form package), which can be in the form of a hydrate, solvate, polymorph or a composition thereof. The kits set forth herein may include a single dose or multiple doses of the compound or pharmaceutical compositions thereof. Kits of the invention can include instructions for using the provided therapeutic dosage forms (e.g., instructions for using the compounds or pharmaceutical compositions included in the kit).
The invention therefore comprises at least the following features:
(i) compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, which can optionally be in the form of a hydrate, solvate or polymorph;
(ii) a method of treatment, comprising administering to a subject (e.g., a human) an effective amount of compound (1), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof (which can optionally be in the form of a hydrate, solvate, or polymorph), to treat a head and neck cancer (e.g., head and neck Squamous Cell Carcinoma (SCCHN), adenoid cystic carcinoma), a breast cancer (e.g., HER 2-negative breast cancer, triple-negative breast cancer), an esophageal cancer (e.g., esophageal adenocarcinoma), a uterine cancer (e.g., uterine sarcoma), an ovarian cancer, a colorectal cancer, a sarcoma (e.g., synovial sarcoma, angiosarcoma, soft tissue sarcoma, fibrosarcoma, uterine sarcoma), a bladder cancer (e.g., urothelial carcinoma), a gastric cancer, a small bowel cancer (e.g., small bowel adenocarcinoma), an endometrial cancer, or a rare;
(iii) a method of treatment comprising administering to a subject (e.g., a human) an effective amount of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof (which can optionally be in the form of a hydrate, solvate or polymorph) for treating a medical disorder responsive to the effects of vascular remodeling and/or anti-CAF activity (e.g., cancer or tumor);
(iv) compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof (which can optionally be in the form of a hydrate, solvate or polymorph) for use in the treatment of squamous cell carcinoma of the head and neck (SCCHN), breast cancer, esophageal cancer, uterine cancer, ovarian cancer, colorectal cancer, sarcoma, bladder cancer, gastric cancer, small intestine cancer, endometrial cancer, or rare cancer;
(v) compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof (which may optionally be in the form of a hydrate, solvate or polymorph) for use in the treatment of a medical condition responsive to the effects of vascular remodeling and/or anti-CAF activity (e.g. cancer or tumour);
(vi) a deuterated derivative of compound (1);
(vii) a method for the preparation of a medicament intended for the therapeutic use for the treatment or prevention of a disorder responsive to the effects of vascular remodeling and/or anti-CAF activity, such as cancer or a tumor, characterized in that compound (1) as set forth above, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, which may optionally be in the form of a hydrate, solvate or polymorph, or an embodiment of the active compound, is used in the preparation;
(viii) compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof in substantially pure (e.g., at least 90% or 95%) form;
(ix) a pharmaceutically acceptable composition of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof (which may optionally be in the form of a hydrate, solvate or polymorph) in a pharmaceutically acceptable carrier or excipient;
(x) A pharmaceutically acceptable dosage form of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof (which may optionally be in the form of a hydrate, solvate or polymorph), optionally in a pharmaceutically acceptable carrier or excipient;
(xi) Compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein it acts by a mechanism other than a vascular remodeling effect and/or anti-CAF action activity, for the treatment of a condition set forth herein; and
(xii) Methods of preparing the compounds described herein and intermediates in the synthesis.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, provide non-limiting examples of the invention.
Figure 1 shows the antitumor effect of compound (1) as monotherapy as set forth in pharmacological test example 4 in the FaDu subcutaneous xenograft model (head and neck cancer) in mice.
Fig. 2 shows the antitumor activity of compound (1) against OSC-19 subcutaneous xenograft model (head and neck cancer) in mice as a monotherapy as set forth in pharmacological test example 5.
Figure 3 shows the antitumor activity of compound (1) as monotherapy as set forth in pharmacological test example 6 against HCC-1806 subcutaneous xenograft (breast cancer) model in mice.
Figure 4 shows the anti-tumor effect of compound (1) in combination with cetuximab in the FaDu subcutaneous xenograft model in mice as described in pharmacological test example 7.
Figure 5 shows the antitumor activity of compound (1) in KPL-4 subcutaneous xenograft model (breast cancer) in mice in combination with trastuzumab as described in pharmacological test example 8.
FIGS. 6A-6B show the antitumor effect of Compound (1) in a mouse model transplanted with HSC-2 orthotherapy. FIG. 6A. transplantation of luciferase-transduced HSC-2 (1X 10) into the tongue of nude mice6Individual cells/spot). Luciferase-transduced HSC-2 amounts were analyzed using an In Vivo Imaging System (IVIS). The data show the bioluminescence levels in the tongue of each mouse. Figure 6b.16 representative bioluminescence images of mice. CDDP, CTX, CDDP + CTX are used as comparators, which are currently used in the treatment of patients with SCCHN cancer. CDDP ═ cisplatin, CTX ═ cetuximab.
FIGS. 7A-7B show the survival advantage of Compound (1) in combination with cetuximab in a HSC-2 orthotopic transplantation mouse model. FIG. 7A. transplantation of luciferase-transduced HSC-2 (1X 10) into the tongue of nude mice6Individual cells/spot). The data show survival curves up to
Figures 8A-8B show the anti-tumor effect of compound (1) in combination with radiation therapy in the FaDu mouse xenograft model. FIG. 8A. subcutaneous implantation of luciferase-transduced FaDu (5X 10) in the right thigh of nude mice6Individual cells/spot). 13 days after vaccination, mice were randomly assigned (n ═ 6) and injected intravenously with 90 μ g/kg of compound (1) on
FIG. 9 shows the anti-tumor activity of Compound (1) in combination with an anti-mPD-1 antibody. C. homogene CT26 s.cCompound (1) and anti-mPD-1 antibody were treated with Q7D schedule and twice-a-week schedule for 3 weeks, respectively, in a mouse model (colon cancer). The results show the tumor volume (mm)3) Average ± SEM (n ═ 8).
Figure 10A shows a cell-free tubulin polymerization assay. The compound (1) has an inhibitory activity on tubulin polymerization. Figure 10B shows microtubule dynamics analysis. Compound (1) also has inhibitory activity on microtubule dynamics.
FIG. 11 shows that Compound (1) is a potent antiproliferative agent in esophageal (OE21, OE33, and TE-8) and uterine (MES-SA, MES-SA/Dx5-Rx1) cell lines.
Figure 12 shows that compound (1) has potent anti-tumor activity as a monotherapy in a subcutaneous xenograft model of breast and ovarian cancer (KPL-4 and COLO-704, respectively).
Figure 13 shows the effect of compound (1) on the tumor microenvironment. As shown, compound (1) increased microvascular density. P <0.05, P <0.01, P <0.0001, relative to untreated (Dunnett) multiple comparison test).
Figure 14 shows the effect of compound (1) on the tumor microenvironment as shown, compound (1) reduced α -SMA positive CAF.
Figure 15 shows that compound (1) reduces ECM protein from CAF in the FaDu subcutaneous xenograft model. FaDu xenograft tumors were collected on
Figure 16 shows that compound (1) exhibits a dose-dependent combination effect with cetuximab in the FaDu subcutaneous xenograft model. Single dose, n-6. Compound (1) and Cetuximab (CTX) were administered on
Figure 17 shows the anti-tumor effect as monotherapy in a soft tissue sarcoma xenograft model in mice. MES-SA (human uterine sarcoma), HT-1080 (human fibrosarcoma) and CTG-2041 (human angiosarcoma) were shown.
Figure 18 shows the anti-tumor effect as monotherapy in a mouse endometrial cancer xenograft model. HEC-108 and AN3CA (endometrial cancer) were shown.
Definition of
As used herein, the term "salt" refers to any and all salts, and encompasses pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al in j.pharmaceutical Sciences,1977,66,1-19 (which is incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, salts of benzoic acid, salts of butyric acid, salts of lactic acid, salts of lauric acid, salts of lauryl acid, salts of malic acid, salts of, Phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4Alkyl radical)4 -And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations, which are formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Compound (1) is also provided and may be administered as the free base.
It is also understood that compounds having the same molecular formula but differing in the nature or order of the bonding of their atoms or in the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in the arrangement of atoms in space are referred to as "stereoisomers".
The terms "composition" and "formulation" are used interchangeably.
A "subject" intended for administration refers to a human (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young, middle aged, or elderly)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., cynomolgus monkey (cynomolgus monkey)) or a cynomolgus monkey (rhesus monkey)), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or an avian (e.g., a commercially relevant avian, such as a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female at any developmental stage. The non-human animal may be a transgenic animal or a genetically modified animal. The term "patient" refers to a human subject in need of treatment for a disease.
The term "administering" or "administration" refers to implanting, absorbing, ingesting, injecting, inhaling or otherwise introducing a compound set forth herein or a composition thereof into or onto a subject.
The terms "treating", "treating" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of the diseases described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have appeared or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms. Treatment may also be continued after symptoms have been alleviated, e.g., to delay or prevent relapse.
An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. An effective amount of a compound described herein may vary depending on factors such as: the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. Alternatively, in a separate method or use, the invention can be used as a prophylactic treatment, where indicated and effective. In certain embodiments, an effective amount is the amount of a compound set forth herein in a single dose. In certain embodiments, an effective amount is the combined amount of a compound set forth herein in multiple doses.
A "therapeutically effective amount" of a compound set forth herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a compound means an amount of a therapeutic agent that provides a therapeutic benefit in the treatment of a disorder, alone or in combination with other therapies. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a disorder, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to treat any of the diseases or conditions set forth.
As used herein, "inhibit (inhibiting," and "inhibitor" and the like refer to the ability of a compound to reduce, slow, stop, or prevent the activity of a biological process, such as tumor growth. In certain embodiments, the inhibition is about 45% to 50%. In certain embodiments, the inhibition is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99.9%, or 100%.
The terms "neoplasm" and "tumor" are used interchangeably herein and refer to a mass of abnormal tissue in which the growth of the mass exceeds and is not coordinated with the growth of normal tissue. A neoplasm or tumor may be "benign" or "malignant," depending on the following characteristics: the degree of cell differentiation (including morphology and functionality), growth rate, local invasion and metastasis. "benign neoplasms" are generally well differentiated, have a slower growth in character than malignant neoplasms and remain localized to the site of origin. In addition, benign neoplasms do not have the ability to infiltrate, invade, or metastasize to distant sites. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characteristically have rapid growth with progressive infiltration, invasion and destruction of surrounding tissues. Furthermore, malignant neoplasms often have the ability to metastasize to distant parts. The term "metastasis" refers to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, and is generally identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or original tumor, rather than the organ or tissue in which the secondary (metastatic) tumor is located.
The term "cancer" refers to a class of diseases characterized by abnormal cellular development that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues.
The term "rare cancer" refers to a cancer that occurs in a relatively small number of patients. Rare cancers include, but are not limited to, sarcomas (e.g., soft tissue sarcoma, liposarcoma, uterine sarcoma, leiomyosarcoma, myxofibrosarcoma, osteosarcoma, angiosarcoma, Ewing's sarcoma, synovial sarcoma, rhabdomyosarcoma), malignant lymphomas, thymus cancers (e.g., thymoma), mesothelioma, gastrointestinal stromal tumor (GIST), neuroendocrine cancers, eye cancers, brain tumors, osteochondral tumors, skin cancers, and germ cell tumors.
The term "anti-cancer agent" refers to any therapeutic agent that can be used to treat cancer (e.g., inhibit cancer or tumor growth in a subject) in a subject. Anticancer agents encompass biotherapeutic anticancer agents as well as chemotherapeutic agents.
Detailed Description
The present invention will be described in detail below with reference to embodiments of the present invention and the like. The present invention provides a compound (e.g., compound (1)), and a pharmaceutically acceptable salt or isotopically labeled derivative thereof, and a pharmaceutical composition thereof. The present invention also provides a method of inhibiting tumor growth and/or treating cancer in a subject comprising administering to the subject an effective amount of a compound or composition provided herein. The compound or composition may be administered as a monotherapy or in combination with another therapy, as set forth herein. In another aspect, the invention provides a process for the preparation of compound (1) and synthetic intermediates useful for this purpose.
The present invention includes compounds of the following structure:
or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, optionally in the form of a hydrate, solvate or polymorph, optionally in a pharmaceutically acceptable carrier or excipient.
Compound (1) may exist as a crystalline polymorph, and the compound of the present invention may be in a single crystalline form or any of a mixture of two or more crystalline forms. Compound (1) may be amorphous, or may be an anhydrate or a solvate, e.g., a hydrate.
The present invention includes isotopically labeled derivatives of compound (1) and pharmaceutically acceptable salts thereof. Isotopically labeled compounds are equivalent to compound (1) except that one or more atoms are replaced by an atom having an atomic mass or mass number different from those atoms typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, bromine and chlorine, for example2H、3H、11C、13C、14C、18F、35S、123I and125I。
isotopically-labelled compounds (e.g. incorporating ligands such as3H and/or14C, etc.) can be used for tissue distribution analysis of drugs and/or substrates. Isotope of carbon monoxide3H and14c is considered useful because the isotope can be readily prepared and detected. Isotope of carbon monoxide11C and18f can be used in PET (positron emission tomography). Isotope of carbon monoxide125I is considered to be useful in SPECT (single photon emission computed tomography), and in brain imaging. From heavier isotopes (e.g. of the type2H) Substitutions yield some advantages in terms of treatment (e.g., prolonged half-life in vivo or reduction in necessary dose) due to their higher metabolic stability, and are therefore considered useful in a given situation. Isotopically labeled compounds can be similarly prepared by employing readily available isotopically labeled reagents rather than non-isotopically labeled reagents and by carrying out the procedures disclosed in the schemes and/or in the examples set forth below.
The compound (1) can be used as a chemical probe for capturing a target protein of a low molecular weight compound having biological activity. Specifically, the compounds of the present invention can be converted into affinity chromatography probes, photoaffinity probes or the like by introducing a labeling group, a linker or the like into a portion other than the structural site necessary for the active expression of the compound by the method set forth in J.Mass Spectrum.Soc.Jpn. Vol.51, 5,2003, p.492-498, W02007/139149 or the like.
Examples of the labeling group, linker or the like used in the chemical probe include groups belonging to the following groups (1) to (5) (1) protein labeling groups such as photoaffinity labeling groups (e.g., benzoyl, benzophenone group, azide group, carbonyl azide group, diazacyclopropane group, enone group, diazo group and nitro group) and chemical affinity groups (e.g., ketone group in which α carbon atoms are substituted with halogen atom, carbamoyl group, ester group, alkylthio group, a, β -unsaturated ketone, ester or the likeMichael (Michael) acceptors and ethylene oxide groups such as these); (2) cleavable linkers such as S-S, O-Si-O, monosaccharides (such as glucosyl or galactosyl) and disaccharides (such as lactose) and oligopeptide linkers cleavable by enzymatic reactions; (3) capturing labelling (fishing) groups such as biotin and 3- (4,4-difluoro-5,7-dimethyl-4H-3a,4 a-diaza-4-boro-sym-indacen-3-yl) propionyl (3- (4,4-difluoro-5,7-dimethyl-4H-3a,4 a-diaza-4-bora-s-indacen-3-yl) propiononyl group); (4) radiolabelled groups, e.g.125I、32P、3H and14c; fluorescent labeling groups such as fluorescein, rose bengal, dansyl (dansyl), umbelliferone, 7-nitrofurazan group and 3- (4,4-difluoro-5,7-dimethyl-4H-3a,4 a-diaza-4-boro-sym-indacen-3-yl) propionyl; chemiluminescent groups, such as luciferin and luminol; and labels capable of detecting heavy metal ions (e.g., lanthanide metal ions and radium ions); and (5) groups that bind to solid supports such as glass beads, glass beds, microliter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, and nylon beds.
Probes prepared by introducing a labeling group selected from the above-mentioned groups (1) to (5) or the like into the compounds of the present invention by the method set forth in any of the above-mentioned documents or the like can be used as chemical probes for identifying marker proteins useful for the study of novel potential drug targets.
Examples of the "salt" used herein include salts with inorganic acids, salts with organic acids, and salts with acidic amino acids, and particularly preferably pharmaceutically acceptable salts. In addition, the salts of the compounds of the present invention encompass the anhydrates and solvates (e.g., hydrates) of the pharmaceutically acceptable salts thereof. Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and preferred examples of the salt with an organic acid include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferred examples of the salt with an acidic amino acid include salts with aspartic acid and glutamic acid and the like.
In the case where the compound (1) of the present invention is obtained as a salt of the compound (1) or a hydrate form of the compound (1), the salt and the hydrate can be converted into an episome of the compound (1) by a conventional method.
Pharmaceutical composition, kit and administration
The present invention provides a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient. In certain embodiments, a compound set forth herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, is provided in a pharmaceutical composition in an effective amount (e.g., a therapeutically effective amount).
The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacy. Generally, these methods of preparation involve bringing into association compound (1) (i.e., "active ingredient") with carriers or excipients and/or one or more other auxiliary ingredients and then, if needed and/or desired, shaping and/or packaging the product into the desired single-dose or multi-dose units. The pharmaceutical composition of the present invention can be prepared according to known methods, for example, methods described in general rules for preparation of the japanese Pharmacopoeia (japanese Pharmacopoeia) 16 th edition, the United States Pharmacopoeia (United States Pharmacopoeia) and the european Pharmacopoeia (european Pharmacopoeia) 9 th edition. Depending on the dosage form, the pharmaceutical composition of the present invention may be suitably administered to a patient.
The pharmaceutical compositions may be prepared, packaged and/or sold in bulk, as a single unit dose, and/or as multiple single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of active ingredient is typically equal to the dose of active ingredient administered to the subject and/or a convenient fraction of the dose (e.g., one-half or one-third of the dose).
The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and/or any other ingredients in the pharmaceutical compositions set forth herein will vary depending on the nature (identity), size, and/or condition of the subject being treated, and further depending on the route of administration of the composition. The composition may comprise between 0.1% and 100% (w/w) active ingredient.
Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binders, preservatives, buffers, lubricants and/or oils. Excipients (e.g., cocoa butter and suppository waxes), colorants, coatings, sweeteners, flavorants, and aromatics may also be present in the compositions.
The compounds provided herein are generally formulated in dosage unit form for ease of administration and uniformity of dosage. However, it will be understood that the total daily amount of the compositions set forth herein will be determined by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors, including the severity of the disease and disorder being treated; the activity of the particular active ingredient used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration and rate of excretion of the particular active ingredient employed; the duration of the treatment; drugs used in combination or concomitantly with the specific active ingredients employed; and similar factors well known in the medical arts.
The compounds of the invention provided herein (compound (1)) and compositions thereof can be administered by any route, including enterally (e.g., oral), parenterally, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, subcutaneously, intraventricularly, transdermally, intradermally (interdidermal), rectally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, cream, and/or drops), mucosally, nasally, buccally, sublingually; by intratracheal instillation, bronchial instillation and/or inhalation; and/or as an oral spray, nasal spray and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via the blood and/or lymphatic supply, and/or direct administration to the affected site. In general, the most appropriate route of administration will depend on a variety of factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
The exact amount of compound (1) required to obtain an effective amount will vary from subject to subject, depending on, for example, the species, age, and general condition of the subject, the severity of the side effects or disorders, the nature of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., a single oral dose) or in multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses comprise different or substantially the same amounts of a compound set forth herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, in non-limiting examples, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell may be three doses a day, two doses a day, one dose every other day, one dose every two days, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks or even slow dose-controlled delivery using a drug delivery device over a selected period of time. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is one dose per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is two doses per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first and last dose of the multiple doses is about or at least one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the entire life stage of the subject, tissue, or cell. In certain embodiments, the duration between the first and last dose of the plurality of doses is about or at least three months, six months, or one year. In certain embodiments, the duration between the first and last dose of the plurality of doses is the entire life stage of the subject, tissue, or cell. In certain embodiments, a dose set forth herein (e.g., any dose of a single dose or multiple doses) independently comprises between 0.001mg/kg and 0.01mg/kg, between 0.01mg/kg and 0.1mg/kg, or between 0.1mg/kg and 1mg/kg, inclusive of compound (1). Examples are dosage forms having at least about 0.01mg, 0.05mg, 0.1mg, 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 10mg, 5mg, 20mg, 25mg or 50mg of the active compound or a salt thereof in the dosage form.
Dosage ranges as set forth herein provide guidance for administering the provided pharmaceutical compositions to adults. The amount to be administered, for example, to a child or adolescent may be determined by a medical practitioner or one skilled in the art and may be lower than or the same as the amount administered to an adult.
Kits (e.g., pharmaceutical packages) are also encompassed by the present disclosure. The provided kits may comprise a pharmaceutical composition or compound (1) and a container (e.g., a vial, ampoule, bottle, syringe and/or dispenser package or other suitable container). In some embodiments, the provided kits may optionally further comprise a second container comprising a pharmaceutical excipient for diluting or suspending a pharmaceutical composition or compound (1). In some embodiments, the pharmaceutical compositions or compounds (1) provided in the first and second containers are combined to form one unit dosage form. The kits described herein may include one or more of the additional agents described herein as separate compositions.
Methods of treatment and uses
As shown herein, compound (1) has significant tumor vascular remodeling effects and anti-CAF activity, and thus, it has potential use for treating cancer and/or inhibiting tumor growth.
Provided herein is a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof. The present invention also provides a compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof, for use in treating cancer in a subject. The present invention also provides the use of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of cancer.
Also provided herein is a method of inhibiting tumor growth in a subject, the method comprising administering to the subject compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof. Also provided herein is compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for use in inhibiting tumor growth in a subject. The invention also provides the use of compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for inhibiting tumor growth.
In certain embodiments of the methods and uses provided herein, the cancer is head and neck cancer, breast cancer, esophageal cancer, uterine cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, small bowel cancer, bladder cancer, or sarcoma.
In certain embodiments of the methods and uses provided herein, the cancer is a cancer of the head and neck (e.g., squamous cell carcinoma of the head and neck, cancer of the oral cavity, cancer of the larynx, cancer of the salivary glands, cancer of the tongue, adenoid cystic carcinoma). In certain embodiments, the cancer is squamous cell carcinoma of the head and neck (SCCHN). In certain embodiments, the cancer is adenoid cystic carcinoma. In certain embodiments, the cancer is breast cancer (e.g., HER2 positive breast cancer, triple negative breast cancer). In certain embodiments, the cancer is HER2 positive breast cancer. In certain embodiments, the cancer is triple negative breast cancer. In certain embodiments, the cancer is colorectal cancer (e.g., colon cancer). In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is esophageal cancer (e.g., esophageal adenocarcinoma). In certain embodiments, the cancer is esophageal adenocarcinoma. In certain embodiments, the cancer is uterine cancer (e.g., uterine sarcoma). In certain embodiments, the cancer is uterine sarcoma. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is a sarcoma (e.g., uterine sarcoma, fibrosarcoma, angiosarcoma, synovial sarcoma, soft tissue carcinoma). In certain embodiments, the cancer is fibrosarcoma. In certain embodiments, the cancer is angiosarcoma. In certain embodiments, the cancer is synovial sarcoma. In certain embodiments, the cancer is a soft tissue cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is an intestinal cancer (e.g., small intestine cancer, small intestine adenocarcinoma). In certain embodiments, the cancer is small bowel cancer. In certain embodiments, the cancer is small bowel adenocarcinoma. In certain embodiments, the cancer is bladder cancer (e.g., urothelial cancer). In certain embodiments, the cancer is urothelial cancer. In certain embodiments, the cancer is endometrial cancer. In certain embodiments, the cancer is a rare cancer.
Combination therapy
In addition to being administered as monotherapy, compound (1) may be administered in combination with other therapeutic agents or modalities. In certain embodiments, the additional therapeutic agent is an antibody. In certain embodiments, the additional therapeutic agent is a monoclonal antibody. The compounds of the invention may be administered in combination with another therapeutic agent, such as an anti-EGFR therapy, an anti-HER 2 therapy, an anti-PD-1 therapy, an anti-PD-L1 therapy, or an irradiation therapy.
In certain embodiments, compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof is administered in combination with an anti-EGFR therapy (e.g., an anti-EGFR monoclonal antibody (mAb), e.g., cetuximab). In certain embodiments, the anti-EGFR therapy is an anti-EGFR antibody. For example, provided herein is a method of treating squamous cell carcinoma of the head and neck (SCCHN) in a subject, comprising administering to the subject a combination of compound (1), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, and an anti-EGFR (epidermal growth factor receptor) mAb therapy. In certain embodiments, the anti-EGFR mAb is Cetuximab (CTX).
In certain embodiments, compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof is administered in combination with an anti-HER 2 therapy (e.g., an anti-HER 2 monoclonal antibody (mAb), e.g., trastuzumab). In certain embodiments, the anti-HER 2 therapy is an anti-HER 2 antibody. For example, provided herein is a method of treating breast cancer in a subject in need thereof comprising administering to the subject compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a composition thereof, in combination with HER2 (human epidermal growth factor receptor) mAb therapy. In certain embodiments, the anti-HER 2mAb is trastuzumab.
In certain embodiments, compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof is administered in combination with an anti-PD-1 or anti-PD-L1 therapy (e.g., an anti-PD-1 or anti-PD-L1 monoclonal antibody). In certain embodiments, the anti-PD-1 or anti-PD-L1 therapy is an antibody. For example, provided herein is a method of treating colorectal cancer in a subject in need thereof, comprising administering to the subject compound (1), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a composition thereof, in combination with an anti-PD-1 or anti-PD-L1 therapy (e.g., mAb therapy).
In certain embodiments, compound (1) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof or a pharmaceutical composition thereof is used in combination with Radiotherapy (RT). In certain embodiments, the compound is administered in combination with surgery.