BioCentury
ARTICLE | Distillery Therapeutics

Cancer

November 9, 2018 9:20 PM UTC

In vitro, cell culture and mouse studies identified a CDK9 inhibitor that could help treat colorectal and other cancers. Screening of a natural product library followed by chemical synthesis and in vitro enzymatic activity assays of analogs of the top hit yielded an aminothiazole-based compound that inhibited CDK9 with an IC50 value of 5 nM. In a panel of human cancer and non-cancer cell lines, the compound decreased proliferation with greater potency in seven cancer lines -- including acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), colorectal, breast and prostate cancers -- than in a non-cancer cell line. In two human colorectal cancer cell lines, the compound decreased colony formation compared with vehicle. In a xenograft mouse model of colorectal cancer, the compound decreased tumor size and increased survival. Next steps include testing the toxicity of the compound and optimizing its formulation for use in AML patients (see “Solid Plans for CDK9”).

Sanofi and Sumitomo Dainippon Pharma Co. Ltd. have alvocidib flavopiridol, a small molecule synthetic flavonoid CDK9 inhibitor, in Phase II testing to treat AML and chronic lymphocytic leukemia (CLL) and Phase I/II testing to treat myelodysplastic syndrome (MDS). Sumitomo also has TP-1287, an oral prodrug of alvocidib, in preclinical testing for AML and solid tumors...

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