BioCentury
ARTICLE | Distillery Therapeutics

Cancer

April 10, 2018 10:56 PM UTC

Cell culture and mouse studies identified p53-activating tetrahydroindazole-based DHODH inhibitors that could help treat melanoma. Screening of a small molecule library in human melanoma cell line-based assays of p53-dependent transcription, followed by chemical synthesis of analogs of a screening hit and in vitro enzyme activity assays, yielded two tetrahydroindazole-based compounds that inhibited DHODH with IC50 values of 1 µM and 11 nM. In the melanoma cell line, the first compound decreased viability compared with no treatment. In a xenograft mouse model of melanoma, the compounds plus a tool compound MDM2 inhibitor decreased tumor growth compared with any agent alone. Next steps include testing screening hits from other compound classes in combination with MDM2 inhibition in models of melanoma.

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