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

摘要

Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound40(JSH-150), which exhibited an IC50of 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). Compound40displayed 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 induce the apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10?mg/kg dosage of40could almost completely suppress the tumor progression. The high selectivity and good in?vivo PK/PD profile suggested that40would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers.