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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Tinghu Zhang1,2, Nicholas Kwiatkowski1,2,3, Calla M Olson1,2

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Nature Chemical Biology
|August 30, 2016
PubMed

Insights

Researchers developed THZ531, a novel inhibitor targeting cyclin-dependent kinases 12 and 13 (CDK12/13). This drug disrupts gene transcription, leading to cancer cell death and offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • Cyclin-dependent kinases 12 and 13 (CDK12/13) are crucial for gene transcription regulation.
  • Lack of specific inhibitors has limited research on CDK12/13 functions in normal and cancer cells.

Purpose of the Study:

  • To rationally design and characterize a first-in-class covalent inhibitor for CDK12 and CDK13.
  • To investigate the effects of CDK12/13 inhibition on gene expression and cell viability.

Main Methods:

  • Rational drug design and synthesis of THZ531.
  • Co-crystallization of THZ531 with CDK12-cyclin K.
  • Analysis of RNA polymerase II phosphorylation and gene expression.
  • Assessment of cell death induction.

Main Results:

  • THZ531 irreversibly inhibits CDK12/13 by targeting an external cysteine residue.
  • Inhibition leads to decreased gene expression, reduced elongating RNA polymerase II, and downregulation of DNA damage response genes.
  • THZ531 treatment induced significant apoptotic cell death.

Conclusions:

  • THZ531 is a potent and selective inhibitor of CDK12 and CDK13.
  • Targeting CDK12/13 with small molecules can induce cancer cell death.
  • This approach may identify cancer subtypes reliant on CDK12/13 activity.

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