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Updated: Nov 17, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents

Hao Shao1, David W Foley1, Shiliang Huang1

  • 1School of Pharmacy and Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

European Journal of Medicinal Chemistry
|February 13, 2021
PubMed

Insights

Researchers developed selective CDK9 inhibitors, potent pyrimidine compounds, showing anti-proliferative effects in solid tumors and leukemia. These inhibitors target Cyclin-dependent kinases (CDKs) crucial for cell cycle and transcription.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Cyclin-dependent kinases (CDKs) regulate cell cycle and transcription.
  • CDK9's role in transcriptional elongation makes it a disease target.
  • Developing selective CDK9 inhibitors is challenging due to conserved ATP binding sites.

Purpose of the Study:

  • Optimize 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors.
  • Evaluate the anti-proliferative activity of these compounds against various cancer cell lines.
  • Investigate the molecular mechanisms of CDK9 inhibition.

Main Methods:

  • Medicinal chemistry optimization of pyrimidine scaffolds.
  • In vitro kinase assays to determine selectivity.
  • Cell-based assays to assess anti-proliferative effects.
  • Western blot analysis to confirm target engagement (CTD phosphorylation, Mcl-1 levels).

Main Results:

  • Compound 30m demonstrated >100-fold selectivity for CDK9 over CDK1 and CDK2.
  • Compounds exhibited broad anti-proliferative activity in solid tumor cell lines and patient-derived CLL cells.
  • Inhibition of RNAPII CTD Ser-2 phosphorylation and Mcl-1 down-regulation were observed.

Conclusions:

  • Optimized pyrimidine compounds are potent and selective CDK9 inhibitors.
  • These inhibitors show therapeutic potential for solid tumors and CLL.
  • Targeting CDK9 impacts key cancer-related pathways.
Keywords:
Anti-Cancer agentsApoptosisCDK9 inhibitorChronic lymphocytic leukaemiaMcl-1RNA polymerase II

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