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. An isolated enantiomer of 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 a direct bond or C 1 -C 4 alkyl;
Z is C 1 -C 4 alkyl or aryl;
R 4 is —OH; and
R 5 is hydrogen or C 1 -C 6 alkyl;
and salts and stereoisomers thereof.
2. The compound of claim 1 , wherein the compound is a slower eluting enantiomer.
3. The compound of claim 1 , wherein the compound is a faster eluting enantiomer.
4. The compound of claim 1 , wherein X 1 is N and X 2 is C.
5. The compound of claim 1 , wherein R 1 is aryl.
6. The compound of claim 1 , wherein R 2 is alkyl.
7. The compound of claim 1 , wherein R 3 is substituted aryl.
8. The compound of claim 1 , wherein R 5 is hydrogen.
9. The compound of claim 1 , wherein Y is C 1 -C 4 alkyl and Z is C 1 -C 4 alkyl.
10. The compound of claim 9 , wherein 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 —.
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 the compound is
13. The compound of claim 12 , wherein the compound is a slower eluting enantiomer.
14. The compound of claim 12 , wherein the compound is a faster eluting enantiomer.
15. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a chemotherapeutic agent.
17. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a therapeutic agent selected from erlotinib, pemetrexed, LY294002, SB431542, and cisplatin.