Compositions and methods for treating cancer

Patent metadata

Field	Value
Publication number	US-12365693-B2
Application number	US-202418956941-A
Country	US
Kind code	B2
Filing date	Nov 22, 2024
Priority date	Apr 10, 2012
Publication date	Jul 22, 2025
Grant date	Jul 22, 2025

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.

First claim

What is claimed is:

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 a substituted or unsubstituted 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 7c 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 ═(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 10c 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 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 each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aryl is independently substituted with a substituent group.

2. The human K-Ras protein of claim 1 , wherein R 1 is substituted monocyclic heteroaryl or substituted 6,5-fused ring heteroaryl or substituted 6,6-fused ring heteroaryl.

3. The human K-Ras protein of claim 1 , wherein R 1 is substituted 6,5-fused ring heteroaryl.

4. The human K-Ras protein of claim 1 , wherein R 1 is selected from 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl, each independently substituted.

5. The human K-Ras protein of claim 2 , wherein each substituent group on the R 1 is independently selected from oxo, 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 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

6. The human K-Ras protein of claim 5 , wherein each substituent group on the R 1 is independently selected from halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —CH 3 , and —CH 2 CH 3 .

7. The human K-Ras protein of claim 3 , wherein each substituent group on the R 1 is independently selected from halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —CH 3 , and —CH 2 CH 3 .

8. The human K-Ras protein of claim 4 , wherein each substituent group on the R 1 is independently selected from halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —CH 3 , and —CH 2 CH 3 .

9. The human K-Ras protein of claim 6 , wherein
f8 is 1 and R 2C is methyl, trifluoromethyl, phenyl, or oxo; or
f8 is 2 and R 2C is methyl.

10. The human K-Ras protein of claim 6 , wherein f8 is 1 and R 2C is methyl.

11. The human K-Ras protein of claim 8 , wherein
f8 is 1 and R 2C is methyl, trifluoromethyl, phenyl, or oxo; or
f8 is 2 and R 2C is methyl.

12. The human K-Ras protein of claim 8 , wherein f8 is 1 and R 2C is methyl.

13. The human K-Ras protein of claim 7 , wherein f8 is 2 and R 2C is methyl.

14. The human K-Ras protein of claim 1 , wherein R 1 is substituted pyridinyl, substituted pyrimidinyl, substituted thiophenyl, substituted furanyl, substituted indolyl, substituted benzoxadiazolyl, substituted benzodioxolyl, substituted benzodioxanyl, substituted thianaphthanyl, substituted pyrrolopyridinyl, substituted indazolyl, substituted quinolinyl, substituted quinoxalinyl, substituted pyridopyrazinyl, substituted quinazolinonyl, substituted benzoisoxazolyl, substituted imidazopyridinyl, substituted benzofuranyl, substituted benzothiophenyl, substituted phenyl, substituted naphthyl, substituted biphenyl, substituted pyrrolyl, substituted pyrazolyl, substituted imidazolyl, substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl, substituted thiazolyl, substituted furylthienyl, substituted pyridyl, substituted pyrimidyl, substituted benzothiazolyl, substituted purinyl, substituted benzimidazolyl, substituted isoquinolyl, substituted thiadiazolyl, substituted oxadiazolyl, substituted pyrrolyl, substituted diazolyl, substituted triazolyl, substituted tetrazolyl, substituted benzothiadiazolyl, substituted isothiazolyl, substituted pyrazolopyrimidinyl, substituted pyrrolopyrimidinyl, substituted benzotriazolyl, or substituted quinolyl.

15. The human K-Ras protein of claim 14 , wherein each substituent group on the R 1 is independently selected from oxo, 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 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

16. The human K-Ras protein of claim 14 , wherein each substituent group on the R 1 is independently selected from halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —CH 3 , and —CH 2 CH 3 .

17. The human K-Ras protein of claim 16 , wherein R 1 is substituted pyridinyl.

18. The human K-Ras protein of claim 1 , wherein R 1 is R 3 -substituted pyridinyl, R 3 -substituted pyrimidinyl, R 3 -substituted thiophenyl, R 3 -substituted furanyl, R 3 -substituted indolyl, R 3 -substituted benzoxadiazolyl, R 3 -substituted benzodioxolyl, R 3 -substituted benzodioxanyl, R 3 -substituted thianaphthanyl, R 3 -substituted pyrrolopyridinyl, R 3 -substituted indazolyl, R 3 -substituted quinolinyl, R 3 -substituted quinoxalinyl, R 3 -substituted pyridopyrazinyl, R 3 -substituted quinazolinonyl, R 3 -substituted benzoisoxazolyl, R 3 -substituted imidazopyridinyl, R 3 -substituted benzof

Assignees

• Univ California

Inventors

• Ostrem Jonathan
• Peters Ulf
• Shokat Kevan M

Classifications

• C12Q2600/158

  Expression markers · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q1/6886

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C07C317/08

  of an acyclic unsaturated carbon skeleton · CPC title

• C07C235/20

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title