Shape-based virtual screen for the discovery of novel CDK8 inhibitor chemotypes

Bioorg Med Chem Lett. 2019 Feb 15;29(4):549-555. doi: 10.1016/j.bmcl.2018.12.065. Epub 2019 Jan 2.

Abstract

With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.

Keywords: Antitumor; CDK8; ROCKs; Virtual screen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / pathology
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • G1 Phase / drug effects
  • HCT116 Cells
  • Humans
  • Molecular Docking Simulation
  • Phosphorylation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • S Phase / drug effects
  • STAT1 Transcription Factor / metabolism

Substances

  • Protein Kinase Inhibitors
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8