JSH-150 is a highly selective CDK9 inhibitor(IC50 : 1 nM).

CDK16-CyclinY:292 nM, CDK14-CyclinY:1.68 μM, CDK5-p25:4.64 μM, CDK2-CyclinA:2.86 μM, CDK9-CyclinT1:1 nM, CDK7-CyclinH-MNAT1:1.72 μM, CDK1-CyclinB:1.34 μM

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 induce the apoptosis in the leukemia cells.

In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression.?The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers.