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Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-05-15 , DOI: 10.1016/j.ejmech.2020.112424 Junyu Xu 1 , Hongmei Li 2 , Xinren Wang 2 , Jianhang Huang 2 , Shuwen Li 2 , Chenhe Liu 2 , Ruinan Dong 2 , Gaoyuan Zhu 2 , Chunqi Duan 2 , Fei Jiang 2 , Yanmin Zhang 3 , Yuqin Zhu 2 , Tianyi Zhang 2 , Yadong Chen 4 , Weifang Tang 5 , Tao Lu 4
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-05-15 , DOI: 10.1016/j.ejmech.2020.112424 Junyu Xu 1 , Hongmei Li 2 , Xinren Wang 2 , Jianhang Huang 2 , Shuwen Li 2 , Chenhe Liu 2 , Ruinan Dong 2 , Gaoyuan Zhu 2 , Chunqi Duan 2 , Fei Jiang 2 , Yanmin Zhang 3 , Yuqin Zhu 2 , Tianyi Zhang 2 , Yadong Chen 4 , Weifang Tang 5 , Tao Lu 4
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Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/αD region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9.
中文翻译：
香豆素衍生物作为具有高抗肿瘤活性的有效和选择性细胞周期蛋白依赖性激酶9（CDK9）抑制剂的发现。
CDK9的特异性抑制被认为是开发有效抗癌疗法的有前途的策略。但是，大多数已报道的CDK9抑制剂仍处于开发的早期阶段，并且对其他CDK缺乏选择性。在本文中，我们发现了香豆素衍生物30i作为高效的CDK9抑制剂，具有很高的选择性（是CDK7的8300倍）。结合模式分析表明，取代香豆素部分是CDK9选择性的关键基团，因为它占据了柔性铰链/αD区，而在其他CDK中空间受阻。化合物30i显示出优异的细胞抗增殖活性，中等的药代动力学特性和低hERG抑制作用。此外，在MV4-11异种移植小鼠模型中，30i以剂量依赖性方式显着诱导肿瘤生长抑制，而不会引起明显的体重减轻。
更新日期：2020-05-15
中文翻译：
香豆素衍生物作为具有高抗肿瘤活性的有效和选择性细胞周期蛋白依赖性激酶9（CDK9）抑制剂的发现。
CDK9的特异性抑制被认为是开发有效抗癌疗法的有前途的策略。但是，大多数已报道的CDK9抑制剂仍处于开发的早期阶段，并且对其他CDK缺乏选择性。在本文中，我们发现了香豆素衍生物30i作为高效的CDK9抑制剂，具有很高的选择性（是CDK7的8300倍）。结合模式分析表明，取代香豆素部分是CDK9选择性的关键基团，因为它占据了柔性铰链/αD区，而在其他CDK中空间受阻。化合物30i显示出优异的细胞抗增殖活性，中等的药代动力学特性和低hERG抑制作用。此外，在MV4-11异种移植小鼠模型中，30i以剂量依赖性方式显着诱导肿瘤生长抑制，而不会引起明显的体重减轻。
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