New CDK8 inhibitors as potential anti-leukemic agents - Design, synthesis and biological evaluation

Bioorg Med Chem. 2020 May 15;28(10):115461. doi: 10.1016/j.bmc.2020.115461. Epub 2020 Mar 27.

Abstract

Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating cell transcription either through its association with the mediator complex or by the phosphorylation of transcription factors. CDK8-mediated activation of oncogenes has proved to be important in a variety of cancer types including hematological malignancies. We have designed and synthesized a series of new synthetic steroids. The compounds were evaluated as CDK8 inhibitors in vitro. The three most potent compounds exhibit Kd-values towards CDK8 in the low nanomolar range (3.5-18 nM). Furthermore, the compounds displayed selectivity for CDK8 in a panel of 465 different kinases. The cell studies indicated a selectivity to kill AML-cancer cell lines compared to normal cell lines.

Keywords: Anti-leukemia; CDK8 inhibition; Steroids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 8 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Steroids / chemical synthesis
  • Steroids / chemistry
  • Steroids / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Steroids
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8