Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore

Bioorg Med Chem Lett. 2016 Mar 1;26(5):1443-51. doi: 10.1016/j.bmcl.2016.01.062. Epub 2016 Jan 22.

Abstract

Here we describe the discovery and optimization of 3-benzylindazoles as potent and selective inhibitors of CDK8, also modulating CDK19, discovered from a high-throughput screening (HTS) campaign sampling the Merck compound collection. The primary hits with strong HSP90 affinity were subsequently optimized to potent and selective CDK8 inhibitors which demonstrate inhibition of WNT pathway activity in cell-based assays. X-ray crystallographic data demonstrated that 3-benzylindazoles occupy the ATP binding site of CDK8 and adopt a Type I binding mode. Medicinal chemistry optimization successfully led to improved potency, physicochemical properties and oral pharmacokinetics. Modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8, was demonstrated in an APC-mutant SW620 human colorectal carcinoma xenograft model following oral administration.

Keywords: CDK19; CDK8; HSP90; Indazoles; Mediator complex; WNT pathway inhibitors.

MeSH terms

  • Animals
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 8 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Indazoles / administration & dosage
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • HSP90 Heat-Shock Proteins
  • Indazoles
  • Protein Kinase Inhibitors
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8