COMBINATION THERAPIES FOR OVERCOMING RESISTANCE TO MITOTIC AGENTS DURING CHEMOTHERAPY

摘要

This disclosure relates to the uses of compounds that target an interaction between CHFR and PARP1. In certain embodiments, the disclosure relate to treating cancer by administering a mitotic inhibitor such as a taxane and a vinca alkaloid in combination with a compound that inhibits CHFR and PARP1 interactions, such as 5-((1-benzyl-1H-indol-3-yl)methylene)-1-(3,4-dimethylphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione, derivatives or salts thereof, optionally in further combination with a third anti-cancer agent.

主权项

1. A pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound comprising Formula I, salts, esters, prodrugs, or derivatives thereof wherein, A is a carbocyclyl, aryl, or heterocyclyl, wherein A is optionally substituted with one or more, the same or different, R20; X1, X2, and X3 are each O or S; R1 is a heterocyclyl or heterocyclyl comprising a nitrogen containing five membered ring wherein the nitrogen is substituted with benzyl wherein R1 is optionally substituted with one or more, the same or different, R20; R2 is hydrogen, alkyl, amino, formyl, carboxy, carbamoyl, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R20; R20 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R20 is optionally substituted with one or more, the same or different, R21; and R21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.