Discovery of potent and selective CDK8 inhibitors through FBDD approach

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4488-4492. doi: 10.1016/j.bmcl.2017.07.080. Epub 2017 Aug 1.

Abstract

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.

Keywords: CDK8; Fragment-based drug discovery (FBDD); Inhibitor.

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 8 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Picolines / chemical synthesis
  • Picolines / chemistry
  • Picolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Ligands
  • Picolines
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8
  • 4-methylpyridine