激酶
化学
体内
IC50型
癌症研究
细胞凋亡
白血病
细胞生长
立体化学
克隆形成试验
皮兰
药理学
生物化学
体外
生物
免疫学
遗传学
作者
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,Jun Ge,Li Wang,Tao Ren,Yuxin Wang,Jing Liu,Qingsong Liu
标识
DOI:10.1016/j.ejmech.2018.09.025
摘要
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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