Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity
Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity
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DOI：
10.1016/j.ejmech.2020.112424
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发表时间：
2020-08-15
影响因子：
6.7
通讯作者：
Lu, Tao
中科院分区：
文献类型：
--
作者：
Xu, Junyu;Li, Hongmei;Lu, Tao
CDK9的特异性抑制被认为是开发有效的抗癌治疗药物的一个有前途的策略。然而，已报道的大多数CDK9抑制剂仍处于早期开发阶段，对其他CDK缺乏选择性。在此，我们发现香豆素衍生物30I是一种高选择性的CDK9抑制剂(是CDK7的8300倍)。结合模式分析表明，取代基香豆素是CDK9选择性的关键基团，占据了在其他CDK中被空间位阻的柔性铰/αD区域。化合物30I具有良好的细胞增殖抑制活性、中等的药代动力学特性和较低的HERG抑制。此外，在MV4-11异种移植小鼠模型中，30I以剂量依赖的方式显著诱导肿瘤生长抑制，而不会导致明显的体重减轻。总之，这些结果表明，30i可能通过选择性地靶向CDK9而作为一种潜在的急性髓系白血病(AML)治疗药物。(C)2020年爱思唯尔·马森公司。版权所有。
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/alpha D 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. (C) 2020 Elsevier Masson SAS. All rights reserved.