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
Summary
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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