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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

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

Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6

Peter L Toogood1, Patricia J Harvey, Joseph T Repine

  • 1Medicinal Chemistry, Cancer Pharmacology, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Peter.toogood2@pfizer.com

Journal of Medicinal Chemistry
|April 2, 2005
PubMed

Insights

Researchers developed highly selective small molecule inhibitors targeting cyclin-dependent kinases 4 and 6 (Cdk4/6) for novel cancer therapies. Compound 43 (PD 0332991) demonstrated excellent selectivity and pharmacokinetic properties, becoming a promising drug candidate.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Cancer Pharmacology

Background:

  • Cyclin-dependent kinases 4 and 6 (Cdk4/6) are key regulators of the cell cycle.
  • Targeting Cdk4/6 with small molecule inhibitors offers a potential therapeutic strategy for cancer.
  • Achieving high selectivity for Cdk4/6 over other kinases is a significant challenge.

Purpose of the Study:

  • To develop highly selective inhibitors of Cdk4/6.
  • To identify novel small molecules for cancer therapy.
  • To evaluate the in vitro and cellular activity of novel Cdk4/6 inhibitors.

Main Methods:

  • Utilized the pyrido[2,3-d]pyrimidin-7-one scaffold for inhibitor design.
  • Synthesized and characterized modified pyrido[2,3-d]pyrimidin-7-one derivatives with a 2-aminopyridine side chain.
  • Assessed kinase inhibition selectivity in vitro and cellular effects, including cell cycle progression.

Main Results:

  • Modified pyrido[2,3-d]pyrimidin-7-ones demonstrated exquisite selectivity for Cdk4/6.
  • The most selective inhibitors induced a G(1) cell cycle block at low concentrations.
  • Compound 43 (PD 0332991) exhibited a favorable selectivity and pharmacokinetic profile.

Conclusions:

  • The 2-aminopyridine modification of pyrido[2,3-d]pyrimidin-7-ones yields highly Cdk4/6-selective inhibitors.
  • Compound 43 (PD 0332991) is a promising drug candidate for cancer treatment.
  • This approach offers a viable strategy for developing targeted cancer therapies.

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