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Updated: Aug 24, 2026

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

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding

Paolo Pevarello1, Maria Gabriella Brasca, Raffaella Amici

  • 1Chemistry Department, Pharmacia Italia, Viale Pasteur 10, 20014 Nerviano (MI), Italy. paolo.pevarello@pharmacia.com

Journal of Medicinal Chemistry
|June 11, 2004
PubMed

Insights

Researchers identified novel compounds that inhibit cyclin-dependent kinases (CDK2/cyclin A/E), crucial for cancer cell growth. A lead compound demonstrated significant antitumor activity in mice without toxicity, offering a promising new cancer therapy.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Cancer cells exhibit abnormal proliferation due to disrupted cell cycle mechanisms.
  • Targeting cyclin-dependent kinases (CDKs) like CDK2/cyclin A and CDK2/cyclin E offers a promising strategy for novel cancer therapies.
  • Inhibiting CDK kinase activity is a key approach to complement existing cancer treatments.

Purpose of the Study:

  • To identify and develop a new class of inhibitors targeting CDK2/cyclin A/E complexes.
  • To optimize initial screening hits through hit-to-lead expansion for enhanced efficacy.
  • To evaluate the in vivo antitumor activity and safety profile of the developed inhibitors.

Main Methods:

  • High-throughput screening to identify initial inhibitor candidates.
  • Hit-to-lead optimization guided by X-ray crystallography and in vitro testing.
  • In vivo efficacy studies using a mouse xenograft model to assess antitumor activity and toxicity.

Main Results:

  • Identification of a novel class of CDK2/cyclin A/E inhibitors.
  • Structure-activity relationship studies leading to the development of compound 41 (PNU-292137).
  • Compound 41 demonstrated nanomolar inhibition of CDK2/cyclin A (IC50 = 37 nM) and significant in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at non-toxic doses.

Conclusions:

  • The developed CDK2/cyclin A inhibitor (PNU-292137) shows potent and specific antitumor activity.
  • This new class of inhibitors represents a promising therapeutic avenue for cancer treatment.
  • The findings support further development of these compounds as novel anticancer agents.

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