Utilizing Molecular Dynamics and Mechanistic Pharmacokinetic Studies in the Design of Selective CDK2 Inhibitors

Targeting HR-positive breast cancer via the inhibition of CDK4 and CDK6 has become the standard of care. However, progression inevitably occurs, and emerging data suggest the implication of CDK2 in this resistance mechanism. As part of our efforts to target this resistance, we embarked on a medicinal chemistry campaign to selectively inhibit CDK2 over the broadly essential CDK1. In order to obtain selectivity against CDK1, we utilized a molecular dynamics approach focused on interaction with a conserved lysine in the active site. Additionally, we uncovered a unique mechanism of clearance driven by both metabolism and efflux in rats and demonstrated that we could counter efflux-driven clearance with high permeability. Our efforts resulted in compound 19, which was potent against CDK2, exhibited good selectivity vs CDK4 and CDK1, and had pharmacokinetic properties that enabled evaluation in a CDK2 xenograft model of cancer, where it achieved nearly 80% tumor growth inhibition.