Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models
Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models
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发现一种新型高选择性 CDK9 激酶抑制剂 (JSH-009)，在临床前急性髓系白血病模型中具有有效的抗肿瘤功效
DOI：
10.1007/s10637-019-00868-3
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发表时间：
2019-12
影响因子：
3.4
通讯作者：
Liu Qingsong
中科院分区：
文献类型：
--
作者：
Wang Li;Hu Chen;Wang Aoli;Chen Cheng;Wu Jiaxin;Jiang Zongru;Zou Fengming;Yu Kailin;Wu Hong;Liu Juan;Wang Wenliang;Wang Zuowei;Wang Beilei;Qi Ziping;Liu Qingwang;Wang Wenchao;Li Lili;Ge Jian;Liu Jing;Liu Qingsong
据报道，急性髓性白血病（AML）由于转录成瘾而易受转录破坏。细胞周期蛋白依赖性激酶9（Cyclin-dependent kinase 9，CDK 9）是一种调节转录延伸的蛋白，作为药物靶点受到广泛关注。尽管几种抑制剂，如alvocidib和dinaciclib，在AML的临床试验中显示出有效的治疗效果，但缺乏对CDK 9和其他CDK的高选择性限制了它们的最佳临床疗效。因此，开发高选择性CDK 9抑制剂对于治疗AML的疗效和安全性仍然是必要的。在这里，我们报告了一种新型的高选择性CDK 9抑制剂，JSH-009，它对CDK 9表现出高效力，并显示出对468种激酶/突变体的高选择性。它还在AML的临床前模型中表现出令人印象深刻的体外和体内抗白血病功效，这使得JSH-009成为阐明CDK 9介导的转录的有用药理学工具和AML的新型治疗候选物。
Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML.
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