Related Experiment Video

Updated: Jan 9, 2026

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

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Discovery of Atirmociclib (PF-07220060): A Potent and Selective CDK4 Inhibitor

Gary M Gallego1, Cynthia Palmer1, Suvi Orr1

  • 1Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, La Jolla, San Diego, California 92121, United States.

Journal of Medicinal Chemistry
|December 5, 2025
PubMed

Insights

New selective cyclin-dependent kinase 4 (CDK4) inhibitors offer effective treatment for advanced breast cancer with reduced neutropenia. PF-07220060 (atirmociclib) shows promise by targeting CDK4 over CDK6, minimizing side effects.

Area of Science:

  • Oncology
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are effective for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.
  • Neutropenia is a common side effect of current CDK4/6 inhibitors, linked to CDK6's role in hematopoiesis.

Purpose of the Study:

  • To discover novel aminopyrimidine-based selective CDK4 inhibitors.
  • To develop potent CDK4 inhibitors with improved safety profiles, specifically reduced neutropenia.

Main Methods:

  • Structure-based drug design and molecular dynamics simulations were employed.
  • Efficiency-based optimization strategies (LipE and LipMetE) guided inhibitor development.
  • In vitro and in vivo studies were conducted to assess potency, selectivity, and efficacy.

Main Results:

  • PF-07220060 (atirmociclib) was identified as a highly potent and selective CDK4 inhibitor.
  • Atirmociclib demonstrated high selectivity for CDK4 over CDK6.
  • The compound showed minimal impact on neutrophils and significant efficacy in a mouse xenograft model.

Conclusions:

  • Selective CDK4 inhibition is a viable therapeutic strategy for HR+/HER2- metastatic breast cancer.
  • Atirmociclib represents a promising therapeutic candidate with an improved safety profile due to its selectivity.
  • Targeting CDK4 specifically may overcome the neutropenia associated with dual CDK4/6 inhibitors.

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