Gary M. Gallego, Cynthia L. Palmer, Suvi T. M. Orr, Louise Bernier, Ping Chen, Sujin Cho-Schultz, Judith G. Deal, Klaus Dress, Martin P. Edwards, Mehran Jalaie, Eric F. Johnson, Robert S. Kania, John C. Kath, Jennifer Lafontaine, Sacha Ninkovic, Neal W. Sach, Hong Shen, Lars Anders, Britton Boras, Fengjuan Cao, Julie Cianfrogna, Loretta M. Cox, Lisa D. Marroquin, Bernadette Pascual, Matthew D. Petroski, Casey L. Quinlan, Aida Sacaan, Na Wei, Sajiv K. Nair
Inhibitors of cyclin-dependent kinases 4 and 6 have been shown to be clinically effective for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced, or metastatic breast cancer. These agents, however, often show neutropenia, likely due to the role of CDK6 in hematopoiesis. Herein described is the discovery of a series of aminopyrimidine-based selective CDK4 inhibitors. Central to our strategy were efficiency-based optimization (LipE and LipMetE), structure-based drug design, and molecular dynamics simulation. The culmination of these efforts resulted in the discovery of PF-07220060 (atirmociclib), which possessed high potency and levels of selectivity for CDK4 over CDK6 that translated to minimal impact on neutrophils while driving efficacy in a mouse ZR75-1 xenograft model.