European Journal of Medicinal Chemistry p. 896 - 916 (2018)
Update date:2022-08-15
Topics:
Wang, Beilei
Wu, Jiaxin
Wu, Yun
Chen, Cheng
Zou, Fengming
Wang, Aoli
Wu, Hong
Hu, Zhenquan
Jiang, Zongru
Liu, Qingwang
Wang, Wei
Zhang, Yicong
Liu, Feiyang
Zhao, Ming
Hu, Jie
Huang, Tao
Ge, Juan
Wang, Li
Ren, Tao
Wang, Yuxin
Liu, Jing
Liu, Qingsong
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 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.
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