Combination therapies for treatment of cancer

• US 10,111,874 B2
• Filed: 09/18/2015
• Issued: 10/30/2018
• 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
• Primary Examiner(s): Javanmard, Sahar
• Application Number:
  US14/858,766
• Publication Number:
  US 20160166571A1
• Time in Patent Office: 1,138 Days
• 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 G12C mutant cancer, the method comprising administering an effective amount of a KRAS G12C mutant modulating compound and an additional therapeutic agent to a subject in need thereof, wherein the KRAS G12C mutant modulating compound has the following structure (I′

b);

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

3. The method of claim 2, wherein the phosphatidylinositol kinase (PI3K) inhibitor is GDC0941, MLN1117, BYL719 (Alpelisib) or BKM120 (Buparlisib).

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

5. The method of claim 4, 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.

8. The method of claim 1, 6 or 7, wherein:

represents a double bond;

Q is —

C(═

O)—

, —

C(═

NR^8′

)-, —

NR⁸C(═

O)-, —

S(═

O)₂- or —

NR⁸S(═

O)₂-;

R⁸ is H, C₁-C₆ alkyl or hydroxylalkyl;

R^8′

is H, —

OH, —

CN or C₁-C₆alkyl; and

R⁹ and R¹⁰ are each independently H, cyano, C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R⁹ and R¹⁰ join to form a carbocyclic or heterocyclic ring.

9. The method of claim 8, wherein Q is —

C(═

O)—

, and R⁹ and R¹⁰ are each H.

10. The method of claim 1, 6 or 7, wherein the G12C mutant modulating compound has the following structure:

11. The method of claim 1, 6 or 7, wherein X and Z are N, and Y is CR⁶.

12. The method of claim 1, 6 or 7, wherein R¹ is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

13. The method of claim 1, 6 or 7, wherein R¹ has one of the following structures:

14. The method of claim 1, 6 or 7, wherein R^2a and R^2b are each independently H or halo.

15. The method of claim 1, 6 or 7, wherein the KRAS G12C mutant modulating compound has one of the following structures:

16. The method of claim 1, 6 or 7, 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.

17. The method of claim 16, wherein the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor.

18. The method of claim 17, wherein the epidermal growth factor receptor (EGFR) inhibitor is Erlotinib, Afatinib or Iressa.

19. The method of claim 1, 6 or 7 wherein the compound and the additional therapeutic agent are co-administered.

20. The method of claim 1, 6 or 7 wherein the compound and the additional therapeutic agent are separately administered.

6. A method for inducing apoptosis in a cell population comprising a KRAS G12C mutant protein, the method comprising administering an effective amount of a KRAS G12C mutant modulating compound and an additional therapeutic agent to the cell population, wherein the KRAS G12C mutant modulating compound has the following structure (I′

b);

7. A method for inhibiting G12C mutant protein in a subject, the method comprising administering an effective amount of a KRAS G12C mutant modulating compound and an additional therapeutic agent to the subject, wherein the KRAS G12C mutant modulating compound has the following structure (I′

b);