Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19,ACS Medicinal Chemistry Letters

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Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-10-22 , DOI: 10.1021/acsmedchemlett.1c00300
John M Hatcher _{1,

2} , Prasanna S Vatsan _{1,

2} , Eric Wang _{1,

2} , Jie Jiang _{1,

2} , Nathanael S Gray ₃

Affiliation

CDK8 and its paralog CDK19 are cyclin-dependent kinases that are core components of the so-called Mediator complex that has essential roles as a positive and negative regulator of gene expression. Several efforts to develop inhibitors have yielded natural and synthetic ATP-competitive compounds including cortistatin A, Sel120, BCD-115, CCT251921 (1), and MSC2530818 (2). Here, we used a hybridization approach starting from CCT251921 and MSC2530818 to derive new inhibitors with the aim of developing highly potent and selective inhibitors of CDK8/19. Initial compounds suffered from rapid aldehyde oxidase-mediated metabolism. This liability was overcome by utilizing a pyrazolopyridine hinge binder with a chlorine at the C-3 position. These efforts resulted in JH-XVI-178 (compound 15), a highly potent and selective inhibitor of CDK8/19 that displays low clearance and moderate oral pharmacokinetic properties.

中文翻译：

CDK8/19高效选择性吡唑并吡啶类抑制剂的开发

CDK8 及其旁系同源物 CDK19 是细胞周期蛋白依赖性激酶，它们是所谓的介体复合物的核心成分，该复合物作为基因表达的正向和负向调节因子具有重要作用。一些开发抑制剂的努力已经产生了天然和合成的 ATP 竞争性化合物，包括皮质抑素 A、Sel120、BCD-115、CCT251921 ( 1 ) 和 MSC2530818 ( 2 )。在这里，我们使用从 CCT251921 和 MSC2530818 开始的杂交方法来衍生新的抑制剂，目的是开发高效和选择性的 CDK8/19 抑制剂。初始化合物遭受快速醛氧化酶介导的代谢。通过使用在 C-3 位具有氯的吡唑并吡啶铰链粘合剂克服了这种不利因素。这些努力导致了 JH-XVI-178（化合物15 )，一种高效和选择性的 CDK8/19 抑制剂，具有低清除率和中等口服药代动力学特性。

更新日期：2021-11-11

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