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Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19.

ABSTRACT: 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.

SUBMITTER: Hatcher JM

PROVIDER: S-EPMC8591729 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19.

Hatcher John M JM Vatsan Prasanna S PS Wang Eric E Jiang Jie J Gray Nathanael S NS

ACS medicinal chemistry letters 20211022 11

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 (<b>1</b>), and MSC2530818 (<b>2</b>). Here, we used a hybridization approach starting from CCT251921 and MSC2530818 to derive new inhibitors with the a ...[more]

PMID: 34795857

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