Small molecule inhibitors of PI3-kinase signaling
Provided are certain 1,2,3-triazole and 1,2,3-triazole dimer analogs of DM-PIT-1 which are second-generation selective non-phosphoinositide small molecule inhibitors of phosphatidylinositol-3,4,5-trisphosphate (PIP3), including 1,2,3-triazoles represented by formula (I) where: Ar represents aryl or heteroaryl; X represents O or S; each of R a , R b , R c , and R d independently represents hydrogen, halogen, C 1 -C 10 alkyl, —OH, —CF 3 , aryl, amino, or nitro; and Ar is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 10 alkyl, —OH, —CF 3 , amino, and nitro. Also provided are pharmaceutical compositions comprising compounds of the invention and a pharmaceutical carrier. Also provided are methods of inhibiting PIP3-mediated signaling in a cell and treating cancer using compounds of the invention.
1. A compound represented by formula (II), or a pharmaceutically acceptable salt thereof
wherein:
R 1 represents methyl or —CF 3 ;
R 2 represents hydrogen, halogen, —OH, methyl, or —CF 3 ; and
X represents O or S.
2. The compound of claim 1 , wherein X is O.
3. The compound of claim 1 , wherein X is S.
4. The compound of claim 1 , wherein R 1 is —CF 3 .
5. The compound of claim 1 , wherein each of R 1 and R 2 is —CF 3 .
6. The compound represented by formula (III), or a pharmaceutically acceptable salt thereof
7. A compound represented by formula (V) or formula (VI), or a pharmaceutically acceptable salt thereof
8. A pharmaceutical composition, comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition, comprising the compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition, comprising the compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is O; each of R 1 and R 2 is methyl, or each of R 1 and R 2 is —CF 3 ; and the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.
12. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.
13. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.
14. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by formula (IV), or a pharmaceutically acceptable salt thereof
wherein the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.