INDOLINONE COMPOUNDS AND USES THEREOF
Indolinone derivative compounds that act as EWS-FLI1 transcription factor inhibitors are provided. Also provided are pharmaceutical compositions of the indolinone derivatives, methods of synthesizing the same, methods of treating using same, and assays for identifying the inhibitors of EWS-FLI1 oncoprotein.
1 . A compound having a structure of Formula (I):
or a stereoisomer, a pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, Cl, —CN and —CF 3 ; wherein A is selected from the group consisting of H and C 1-6 alkyl; wherein D is selected from the group consisting of —OH and —O(C 1-6 alkyl); wherein R 5 and R 6 are independently selected from the group consisting of H, F, and C 1-6 alkyl, or wherein R 5 and R 6 taken together form a substituted or unsubstituted cycloalkyl ring; wherein R 12 is independently selected from the group consisting of C 3-8 cycloalkyl and
wherein R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of H, halogen, CN, CF 3 , C 1-6 alkyl, aryl, heteroaryl, —O(aryl), —O(heteroaryl), —CO 2 H, —CO 2 (C 1-6 alkyl), —NHSO 2 (C 1-6 alkyl), —NHSO 2 (aryl), —NHCONH(C 1-6 alkyl), —NHCON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl)CONH 2 , —N(C 1-6 alkyl)CONH(C 1-6 alkyl), —N(C 1-6 alkyl)CON(C 1-6 alkyl) 2 , —SO 2 (C 1-6 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , C 3-8 cycloalkyl, and C 3-8 heterocyclo alkyl.
2 . The compound of claim 1 , wherein R 9 is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, and morpholinolyl.
3 . The compound of claim 1 , wherein R 9 is selected from the group consisting of isopropyl and cyclopropyl.
4 . The compound of claim 1 , having a structure of Formula (Ia):
or a stereoisomer, a pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H and Cl; wherein R 7 , R 8 , R 10 and R 11 are independently selected from the group consisting of H and halogen; and wherein R 9 is independently selected from the group consisting C 3-8 cycloalkyl and C 3-8 heterocycloalkyl.
5 . The compound of claim 1 , wherein R 1 and R 4 are Cl and R 2 and R 3 are H.
6 . The compound of claim 1 , selected from the group consisting of:
or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
7 . The compound of claim 6 , selected from the group consisting of:
or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
8 . The compound of claim 1 , selected from the group consisting of:
or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
9 . The compound of claim 1 , selected from the group consisting of:
or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
10 . The compound of claim 1 , having the structure:
or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
11 . The compound of claim 1 , having the structure:
or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
12 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
13 . A method for inhibiting proliferation of a cell, wherein the cell overexpresses an ETS gene or comprises an ETS fusion gene, comprising contacting the cell with an effective amount of the compound of claim 1 .
14 . The method of claim 13 , wherein the ETS gene or the ETS fusion gene is selected from the group consisting of FLI1, ERG, ETV1, and ETV4.
15 . The method of claim 13 , wherein the cell is a cancer cell, wherein the cancer is selected from the group consisting of Ewing's sarcoma, prostate cancer, glioblastoma, acute myeloid leukemia, breast cancer, head cancer, neck cancer, melanoma, non-small cell lung cancer, ovarian cancer, and uterine cancer.
16 . The method of claim 13 , wherein the cell is mammalian.
17 . A method of killing or inhibiting the growth of a neoplastic cell, comprising contacting the cell with an effective amount of the compound of claim 1 .
18 . The method of claim 17 , wherein the cell is a cancer cell, wherein the cancer is selected from the group consisting of Ewing's sarcoma, prostate cancer, glioblastoma, acute myeloid leukemia, breast cancer, head cancer, neck cancer, melanoma, non-small cell lung cancer, ovarian cancer, and uterine cancer.
19 . The method of claim 17 , wherein the cell is mammalian.