COMBINATION THERAPIES FOR TREATMENT OF CANCER

• US 20160166571A1
• Filed: 09/18/2015
• Published: 06/16/2016
• Est. Priority Date: 09/18/2014
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Janes, Matthew Robert, Patricelli, Matthew Peter, Li, Liansheng, Ren, Pingda, Liu, Yi
• Granted Patent: US 10,111,874 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Combination therapies for treatment of cancers associated with mutations in the KRAS gene are provided. Compositions comprising therapeutic agents for treatment of cancers associated with mutations in the KRAS gene are also provided.

Claims

1. A method for treating a KRAS, HRAS or NRAS G12C mutant cancer, the method comprising administering an effective amount of a KRAS, HRAS or NRAS G12C mutant modulating compound and an additional therapeutic agent to a subject in need thereof.

2. The method of claim 1, wherein the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, Janus kinase (JAK) inhibitor, a Met kinase (MET) inhibitor, a SRC family kinase (SFK) inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, mechanistic target of rapamycin (mTOR) inhibitor, a topoisomerase inhibitor, a taxane, an anti-metabolite agent, an alkylating agent or a taxane.

3. The method of claim 1, wherein the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor.

4. The method of claim 3, wherein the epidermal growth factor receptor (EGFR) inhibitor is Erlotinib, Afatinib or Iressa.

5. The method of claim 1, wherein the additional therapeutic agent is a phosphatidylinositol-3 kinase (PI3K) inhibitor.

6. The method of claim 5, wherein the phosphatidylinositol kinase (PI3K) inhibitor is GDC0941, MLN1117, BYL719 (Alpelisib) or BKM120 (Buparlisib).

7. The method of claim 1, wherein the additional therapeutic agent is an Janus kinase (JAK) inhibitor selected from CYT387, GLPG0634, Baricitinib, Lestaurtinib, momelotinib, Pacritinib, Ruxolitinib, and TG101348.

8. The method of claim 1, wherein the additional therapeutic agent is an MET kinase inhibitor selected from Crizotinib, tivantinib, AMG337, cabozantinib, foretinib, and neutralizing monoclonal antibodies to MET.

9. The method of claim 1, wherein the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor.

10. The method of claim 9, wherein the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541.

11. The method of claim 1, wherein the additional therapeutic agent is a non-receptor tyrosine kinase inhibitor.

12. The method of claim 9, wherein the non-receptor tyrosine kinase inhibitor is an SFK inhibitor.

13. The method of claim 12, wherein the SFK inhibitor is Dasatinib, Ponatinib, saracatinib, or bosutinib.

14. The method of claim 1, wherein the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor.

15. The method of claim 14, wherein the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, cobimetinib, PD0325901, or RO5126766.

16. The method of claim 1, wherein the additional therapeutic agent is a protein kinase inhibitor.

17. The method of claim 14, wherein the protein kinase inhibitor is Afatinib, Axitinib, Bevacizumab, Bostutinib, Cetuximab, Crizotinib, Dasatinib, Erlotinib, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib, Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunitinib, SU6656, Trastuzumab, Tofacitinib, Vandetanib or Vemurafenib.

18. The method of claim 1, wherein the additional therapeutic agent is a topoisomerase inhibitor.

19. The method of claim 18, wherein the topoisomerase inhibitor is Irinotecan.

20. The method of claim 1, wherein the additional therapeutic agent is a taxane.

21. The method of claim 20, wherein the taxane is Taxol or Docetaxel.

22. The method of claim 1, wherein the additional therapeutic agent is an mTOR inhibitor.

23. The method of claim 22, wherein the mTOR inhibitor is Rapamycin or MLN0128.

24. The method of claim 1, wherein the compound selectively binds to KRAS, HRAS or NRAS G12C mutant proteins.

25. The method of claim 1, wherein the compound irreversibly binds to KRAS, HRAS or NRAS G12C mutant proteins.

26. The method of claim 1, wherein the compound covalently binds to KRAS, HRAS or NRAS G12C mutant proteins.

27. The method of claim 1, wherein the compound forms a covalent bond with a cysteine at the 12 position of a KRAS, HRAS or NRAS G12C mutant protein.

28. The method of claim 1, wherein the compound comprises:

(a) a moiety capable of specifically binding to a Switch 2 binding pocket of a KRAS, HRAS or NRAS G12C mutant protein; and

(b) an electrophilic moiety capable of covalent bond formation with a cysteine at the 12 position of the KRAS, HRAS or NRAS G12C mutant protein.

29. The method of claim 1, wherein the compound has the following structure (I):

30. The method of claim 1, wherein the compound has the following structure (II):

31. The method of claim 1, wherein the compound has the following structure (III):

32. The method of claim 28, wherein the electrophilic moiety has the following structure:

33. The method of claim 1, wherein the compound is a compound from any one of Tables 1, 2 or 3.

34. The method of claim 1, wherein the compound has one of the following structures:

35. The method of claim 1, wherein the compound and the additional therapeutic agent are co-administered.

36. The method of claim 1, wherein the compound and the additional therapeutic agent are separately administered.

37. The method of claim 1, wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

50. The method of claim 29, wherein the electrophilic moiety has the following structure:

51. The method of claim 30, wherein the electrophilic moiety has the following structure:

52. The method of claim 31, wherein the electrophilic moiety has the following structure:

38. A method for inducing apoptosis in a cell population comprising a KRAS, HRAS or NRAS G12C mutant protein, the method comprising administering an effective amount of a KRAS, HRAS or NRAS G12C mutant modulating compound and an additional therapeutic agent.

39-40. -40. (canceled)

41. A method for inhibiting tumor metastasis in a subject having a KRAS, HRAS or NRAS G12C mutant cancer, the method comprising administering an effective amount of a KRAS, HRAS or NRAS G12C mutant modulating compound and an additional therapeutic agent.

42-43. -43. (canceled)

44. A pharmaceutical composition comprising a KRAS, HRAS or NRAS G12C mutant modulating compound and an additional therapeutic agent.

45-46. -46. (canceled)

47. A kit comprising a KRAS, HRAS or NRAS G12C mutant modulating compound, an additional therapeutic agent and directions for use of the compound and the additional therapeutic agent for treatment of cancer.

48-49. -49. (canceled)