Related Experiment Video

Updated: Nov 2, 2025

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

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Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer

Kevin D Freeman-Cook1, Robert L Hoffman1, Douglas C Behenna1

  • 1Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, California 92121, United States.

Journal of Medicinal Chemistry
|June 10, 2021
PubMed

Insights

Researchers optimized CDK2/4/6 inhibitors using structure-based design, identifying PF-06873600 as a promising cancer treatment candidate that advanced to clinical trials.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Selective CDK4/6 inhibitors are effective for breast cancer treatment.
  • Resistance to CDK4/6 inhibitors necessitates exploring other cell cycle targets.
  • Broad-spectrum CDK inhibitors have historically faced safety issues.

Purpose of the Study:

  • To develop novel CDK inhibitors targeting additional cell cycle isoforms.
  • To overcome resistance to existing therapies and expand treatment options.
  • To identify a safe and effective CDK inhibitor candidate for clinical development.

Main Methods:

  • Structure-based drug design and Free-Wilson analysis were employed to optimize inhibitors.
  • Molecular dynamics simulations were used to assess selectivity against CDK9.
  • Inhibitor potency, selectivity, and ADME profiles were evaluated.

Main Results:

  • A series of CDK2/4/6 inhibitors were successfully optimized.
  • Molecular dynamics simulations provided insights into CDK9 selectivity.
  • PF-06873600 demonstrated favorable potency, selectivity, and ADME properties.

Conclusions:

  • PF-06873600 (compound 22) was identified as a promising drug candidate.
  • The developed inhibitors offer potential for treating various cancers.
  • PF-06873600 has advanced to phase 1 clinical trials for cancer treatment.

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