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- W3140301085 endingPage "113391" @default.
- W3140301085 startingPage "113391" @default.
- W3140301085 abstract "CDK8 is deregulated in multiple types of human cancer and is viewed as a therapeutic target for the treatment of the disease. Accordingly, the search for small-molecule inhibitors of CDK8 is being intensified. Capitalising on our initial discovery of AU1-100, a potent CDK8 inhibitor yet with a limited degree of kinase selectivity, a structure-based optimisation was carried out, with a series of new multi-substituted pyridines rationally designed, chemically prepared and biologically evaluated. Such endeavour has culminated in the identification of 42, a more potent CDK8 inhibitor with superior kinomic selectivity and oral bioavailability. The mechanism underlying the anti-proliferative effect of 42 on MV4-11 cells was studied, revealing that the compound arrested the G1 cell cycle and triggered apoptosis. The low risk of hepato- and cardio-toxicity of 42 was estimated. These findings merit further investigation of 42 as a targeted cancer therapeutic." @default.
- W3140301085 created "2021-04-13" @default.
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- W3140301085 date "2021-06-01" @default.
- W3140301085 modified "2023-10-18" @default.
- W3140301085 title "Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation" @default.
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- W3140301085 doi "https://doi.org/10.1016/j.ejmech.2021.113391" @default.
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