1. Academic Validation
  2. Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19

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.
John M Hatcher 1 2 Prasanna S Vatsan 1 2 Eric Wang 1 2 Jie Jiang 1 2 Nathanael S Gray 3
Affiliations

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139875
    98.16%, CDK抑制剂
    CDK