Targeting GLI proteins in human cancer by small molecules
The present disclosure provides compositions, pharmaceutical preparations and methods for the diagnosis and treatment of cancers expressing a GLI polypeptide. The disclosed compositions and pharmaceutical preparations may comprise one or more pyrazolyl-containing compounds, or an analog or derivative thereof.
1. A compound of formula (I):
wherein
each of X 1 and X 2 is independently N or C, wherein one of X 1 and X 2 is N and one of X 1 and X 2 is C, such that the ring N forms a double bond with whichever of X 1 and X 2 is C;
R 1 is aryl or substituted aryl;
R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, and alkyl;
R 3 is aryl or substituted aryl;
Y is C 1 -C 4 alkyl and Z is C 1 -C 4 alkyl, such that Y and Z form —CH 2 ) 3 —C(CH 3 ) 2 —CH 2 —;
R 4 is —OH; and
R 5 is hydrogen or C 1 -C 6 alkyl;
and salts, hydrates, solvates, and prodrugs thereof.
2. The compound of claim 1 , wherein X 1 is N and X 2 is C.
3. The compound of claim 1 , wherein X 1 is C and X 2 is N.
4. The compound of claim 1 , wherein R 1 is aryl.
5. The compound of claim 1 , wherein R 2 is selected from aryl, substituted aryl, heteroaryl, and alkyl.
6. The compound of claim 1 , wherein R 2 is selected from heteroaryl and alkyl.
7. The compound of claim 1 , wherein R 3 is aryl.
8. The compound of claim 1 , wherein R 3 is substituted aryl.
9. The compound of claim 1 , wherein R 5 is hydrogen.
10. The compound of claim 1 , wherein R 1 is aryl, R 2 is heteroaryl, and R 3 is aryl.
11. The compound of claim 1 , wherein R 1 is aryl, R 2 is alkyl, and R 3 is substituted aryl.
12. The compound of claim 1 , wherein R 1 is aryl, R 2 is aryl, and R 3 is substituted aryl.
13. The compound of claim 1 , wherein R 1 is aryl, R 2 is substituted aryl, and R 3 is substituted aryl.
14. The compound of claim 1 , wherein the compound is 1,3-diphenyl-5-thiophen-3-yl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, having the structure:
15. The compound of claim 1 , wherein the compound is 3-(4-fluoro-phenyl)-1-phenyl-5-propyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, having the structure:
16. The compound of claim 1 , wherein the compound is 3-(4-fluoro-phenyl)-5-(3-fluoro-phenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, having the structure:
17. The compound of claim 1 , wherein the compound is
(3-(4-fluoro-phenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, Compound 5).
18. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a chemotherapeutic agent.
20. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a therapeutic agent selected from erlotinib, pemetrexed, LY294002, SB431542, and cisplatin.
21. A method for treating a subject with a cancerous condition, the method comprising:
(a) administering to the subject a therapeutically effective amount of the compound of claim 1 ,
wherein the cancerous condition is characterized by expressing a GLI protein, and wherein the administering results in treatment of the subject.
22. A method for treating a subject with a cancerous condition, the method comprising:
(a) administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 18 ,
wherein the cancerous condition is characterized by expressing a GLI protein, and wherein the administering results in treatment of the subject.
23. The compound of claim 1 , wherein the compound is