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

John M Hatcher; Prasanna S Vatsan; Eric Wang; Jie Jiang; Nathanael S Gray

doi:10.1021/acsmedchemlett.1c00300

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

ACS Med Chem Lett. 2021 Oct 22;12(11):1689-1693. doi: 10.1021/acsmedchemlett.1c00300. eCollection 2021 Nov 11.

Authors

John M Hatcher^{1

2}, Prasanna S Vatsan^{1

2}, Eric Wang^{1

2}, Jie Jiang^{1

2}, Nathanael S Gray³

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
² Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
³ Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford University, Stanford, California 94305, United States.

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.