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

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.