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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

Trevor Dale1, Paul A Clarke2, Christina Esdar3

  • 1School of Bioscience, Cardiff University, Cardiff, UK.

Nature Chemical Biology
|October 27, 2015
PubMed

Insights

Researchers developed CCT251545, a selective chemical probe for CDK8 and CDK19 kinases. This WNT pathway inhibitor shows potent cell-based and in vivo activity in WNT-dependent tumors, offering a tool for disease research.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The Mediator complex plays a role in human pathologies, but chemical tools to study it are lacking.
  • Cyclin-dependent kinase 8 (CDK8) and CDK19 are key components of the Mediator complex, implicated in various diseases.

Purpose of the Study:

  • To identify and characterize a novel small-molecule inhibitor targeting CDK8 and CDK19.
  • To evaluate the utility of this inhibitor as a chemical probe for studying the WNT pathway and associated diseases.

Main Methods:

  • Cell-based screening to discover WNT pathway inhibitors.
  • Biochemical assays to determine kinase selectivity and binding mode (X-ray crystallography).
  • In vitro and in vivo studies to assess cellular activity, gene expression changes, and tumor efficacy.

Main Results:

  • CCT251545 was identified as a potent and selective inhibitor of CDK8 and CDK19 (>100-fold selectivity over 291 kinases).
  • X-ray crystallography revealed a type 1 binding mode for CCT251545.
  • CCT251545 demonstrated potent cell-based activity, modulated WNT pathway gene expression, and affected STAT1 phosphorylation.
  • In vivo studies confirmed the activity of CCT251545 in WNT-dependent tumors.

Conclusions:

  • CCT251545 is a valuable chemical probe for CDK8 and CDK19, offering a tool to investigate their roles in human diseases.
  • The compound exhibits promising therapeutic potential for WNT-dependent cancers.

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