Journal article

Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor.

Beilei Wang, Jiaxin Wu, Yun Wu, Cheng Chen, Fengming Zou, Aoli Wang, Hong Wu, Zhenquan Hu, Zongru Jiang, Qingwang Liu, Wei Wang, Yicong Zhang, Feiyang Liu, Ming Zhao, Jie Hu, Tao Huang, Juan Ge, Li Wang, Tao Ren, Yuxin Wang Show all

European Journal of Medicinal Chemistry | Published : 2018

Abstract

Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300-10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1) = 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of MCL-1 and c-Myc, arrest the cell cycle and ind..

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University of Melbourne Researchers