CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors

Eur J Med Chem. 2019 Feb 15:164:77-91. doi: 10.1016/j.ejmech.2018.11.076. Epub 2018 Dec 21.

Abstract

Cyclin-dependent kinases 8 (CDK8) regulates transcriptional process via associating with the mediator complex or phosphorylating transcription factors (TF). Overexpression of CDK8 has been observed in various cancers. It mediates aberrant activation of Wnt/β-catenin signaling pathway, which is initially recognized and best studied in colorectal cancer (CRC). CDK8 acts as an oncogene and represents a potential target for developing novel CDK8 inhibitors in cancer therapeutics. However, other study has revealed its contrary role. The function of CDK8 is context dependent. Even so, a variety of potent and selective CDK8 inhibitors have been discovered after crystal structures were resolved in two states (active or inactive). In this review, we summarize co-crystal structures, biological mechanisms, dysregulation in cancers and recent progress in the field of CDK8 inhibitors, trying to offer an outlook of CDK8 inhibitors in cancer therapy in future.

Keywords: CDK8 inhibitors; Cancer; Overexpression; Selectivity.

Publication types

  • Review

MeSH terms

  • Colorectal Neoplasms / drug therapy
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 8 / chemistry
  • Cyclin-Dependent Kinase 8 / metabolism
  • Drug Discovery
  • Humans
  • Mediator Complex / metabolism
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Oncogenes
  • Protein Kinase Inhibitors / therapeutic use*
  • Wnt Signaling Pathway

Substances

  • Mediator Complex
  • Protein Kinase Inhibitors
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8