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
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
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4-(((4-(5-氯-2-(((1s,4s)-4-((2-甲氧基乙基)氨基)环己基)氨基)吡啶-4-基)噻唑-2-基)的发现
DOI：
10.1016/j.ejmech.2018.09.025
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发表时间：
2018-10-05
影响因子：
6.7
通讯作者：
Liu, Qingsong
中科院分区：
文献类型：
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作者：
Wang, Beilei;Wu, Jiaxin;Liu, Qingsong
通过结构导向的合理药物设计方法，我们发现了一种高度选择性的抑制剂化合物40（JSH-150），其在生化测定中对CDK 9激酶的IC 50为1 nM，并且比其他CDK激酶家族成员具有约300-10000倍的选择性。此外，它还显示出对其他468种激酶/突变体的高选择性（KINOMEscan S评分（1）= 0.01）。化合物40对黑色素瘤、神经母细胞瘤、肝癌、结肠癌、肺癌以及白血病细胞系显示出有效的抗增殖作用。能剂量依赖性地抑制白血病细胞RNA Pol II磷酸化，抑制MCL-1和c-Myc表达，阻滞细胞周期，诱导细胞凋亡。在接种MV 4 -11细胞的异种移植小鼠模型中，10 mg/kg剂量的40几乎可以完全抑制肿瘤进展。高选择性和良好的体内PK/PD特征表明，40将是研究CDK 9介导的生理学和病理学的良好药理学工具，以及白血病和其他癌症的潜在候选药物。(C)2018年Elsevier Masson SAS。All rights reserved.
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. (C) 2018 Elsevier Masson SAS. All rights reserved.