IP Library › Granted Patent US 11,718,630
Granted Patent B2
US 11,718,630 · App. 18/050,269 · Granted Aug 8, 2023

Compositions and methods for treating cancer

Inventors: Jonathan Ostrem (San Francisco, CA); Ulf Peters (San Francisco, CA); Kevan M. Shokat (San Francisco, CA)
Assignee: The Regents of the University of California
C07D495/04A61K38/1709C07C235/20C07C317/08C07D207/14C07D211/58C07D211/62C07D231/40C07D295/185C07D295/26C07D401/04C07D401/06C07D401/12C07D405/12C07D409/04C07D413/12C07D417/12C07D471/10C07D487/04C07D487/10C12N9/14C12Q1/6886C12Q2600/156C12Q2600/158C12Y306/05002G01N2500/04
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Quick Facts
Patent No.
US 11,718,630
App. No.
18/050,269
Granted
Aug 8, 2023
Kind
B2
Abstract

K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer.

Claims (83)

1. A human K-Ras protein having a cysteine at residue 12, wherein said cysteine is covalently bonded to a compound, wherein said compound has the formula

R 1 -L 1 -L 2 -L 3 -E,

wherein

R 1 is substituted or unsubstituted fused ring aryl or substituted or unsubstituted fused ring heteroaryl;

L 1 is substituted or unsubstituted heteroarylene;

L 2 is a bond;

L 3 is

wherein

f8 is an integer from 0 to 8;

each R 2C is independently oxo, halogen, —CX c 3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7c R 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O)—OR 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c C═(O)R 9c , —NR 7c C(O)—OR 9c , —NR 7c OR 9c , —OCX c 3 , —OCHX c 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein two adjacent R 2C substituents are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each R 7c , R 8c , R 9c and R 10c is independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 7c and R 8c are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

m3 and v3 are independently an integer from 1 to 2;

n3 is independently an integer from 0 to 4;

X c is independently —Cl, —Br, —I, or —F; and,

prior to covalently bonding to the cysteine 12,

E is,

wherein R 13 is hydrogen, halogen, —CX b 3 , —CN, —SO 2 Cl, —SO r R 17 , —SO p NR 14 R 15 , —NHNH 2 , —ONR 14 R 15 , —NHC═(O)NHNH 2 , —NHC(O)NR 14 R 15 , —N(O) q , —NR 14 R 15 , —C(O)R 16 , —C(O)—OR 16 , —C(O)NR 14 R 15 , —OR 17 , —NR 14 SO 2 R 17 , —NR 14 C═(O)R 16 , —NR 14 C(O)—R 16 , —NR 14 OR 16 , —OCX b 3 , —OCHX b 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

wherein R 14 , R 15 , R 16 , and R 17 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

wherein R 14 and R 15 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

wherein p is 1 or 2;

wherein q is an integer from 1 to 2;

wherein r is an integer from 0 to 4;

wherein X b is independently Cl, Br, I, or F; and

wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, and substituted aryl is independently substituted with a substituent group.

2. The human K-Ras protein of claim 1 , wherein R 13 is hydrogen, —F, —Cl, —Br, —I, —CX b 3 , or —CN, and X b is —Cl, —Br, —I, or —F.

3. The human K-Ras protein of claim 1 , wherein R 13 is —F, —Cl, —Br, or —I.

4. The human K-Ras protein of claim 1 , wherein R 13 is —F.

5. The human K-Ras protein of claim 2 , wherein R 1 is substituted fused ring aryl.

6. The human K-Ras protein of claim 2 , wherein R 1 is

wherein

e7 is an integer from 0 to 7;

R 3 is independently halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

m and v are independently 1 or 2;

n is independently an integer from 0 to 4; and

each X is independently —Cl, —Br, —I, or —F.

7. The human K-Ras protein of claim 2 , wherein R 1 is

wherein e7 is 1, and R 3 is halogen, —OH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

8. The human K-Ras protein of claim 2 , wherein R 1 is

wherein e7 is 1, and R 3 is halogen.

9. The human K-Ras protein of claim 7 , wherein at least one R 2C is a substituted alkyl.

10. The human K-Ras protein of claim 7 , wherein at least one R 2C is an alkyl substituted with —CN.

11. The human K-Ras protein of claim 3 , wherein R 1 is substituted fused ring aryl.

12. The human K-Ras protein of claim 3 , wherein R 1 is

wherein

e7 is an integer from 0 to 7;

R 3 is independently halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

m and v are independently 1 or 2;

n is independently an integer from 0 to 4; and

each X is independently —Cl, —Br, —I, or —F.

13. The human K-Ras protein of claim 3 , wherein R 1 is

herein e7 is 1, and R 3 is halogen, —OH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

14. The human K-Ras protein of claim 3 , wherein R 1 is

wherein e7 is 1, and R 3 is halogen.

15. The human K-Ras protein of claim 3 , wherein R 1 is

wherein e7 is 1, and R 3 is —Cl.

16. The human K-Ras protein of claim 13 , wherein at least one R 2C is a substituted alkyl.

17. The human K-Ras protein of claim 13 , wherein at least one R 2C is an alkyl substituted with —CN.

18. The human K-Ras protein of claim 14 , wherein at least one R 2C is a substituted alkyl.

19. The human K-Ras protein of claim 14 , wherein at least one R 2C is an alkyl substituted with —CN.

20. The human K-Ras protein of claim 15 , wherein at least one R 2C is a substituted alkyl.

21. The human K-Ras protein of claim 15 , wherein at least one R 2C is an alkyl substituted with —CN.

22. The human K-Ras protein of claim 4 , wherein R 1 is substituted fused ring aryl.

23. The human K-Ras protein of claim 4 , wherein R 1 is

wherein

e7 is an integer from 0 to 7;

R 3 is independently halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

m and v are independently 1 or 2;

n is independently an integer from 0 to 4; and

each X is independently —Cl, —Br, —I, or —F.

24. The human K-Ras protein of claim 4 , wherein R 1 is

wherein e7 is 1, and R 3 is halogen, —OH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

25. The human K-Ras protein of claim 4 , wherein R 1 is

wherein e7 is 1, and R 3 is halogen.

26. The human K-Ras protein of claim 4 , wherein R 1 is

wherein e7 is 1, and R 3 is —Cl.

27. The human K-Ras protein of claim 25 , wherein at least one R 2C is a substituted alkyl.

28. The human K-Ras protein of claim 25 , wherein at least one R 2C is an alkyl substituted with —CN.

29. The human K-Ras protein of claim 26 , wherein at least one R 2C is a substituted alkyl.

30. The human K-Ras protein of claim 26 , wherein at least one R 2C is an alkyl substituted with —CN.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 16, 2023
From: OSTREM, JONATHAN; PETERS, ULF; SHOKAT, KEVAN M.
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 063648/0764 →
Continuity (9)
Continuation 17212737 · Mar 25, 2021
Continuation 16720526 · Dec 19, 2019
Continuation 16013271 · Jun 20, 2018
Continuation 14934184 · Nov 6, 2015
Continuation 14391369
Provisional Application 61794956 · Mar 15, 2013
Provisional Application 61728145 · Nov 19, 2012
Provisional Application 61622507 · Apr 10, 2012
Related Publication 20230135350A1 · May 4, 2023
Cited By (2)
US 12,365,693 US 12,528,818