Elucidating Binding Selectivity in Cyclin-Dependent Kinases 4, 6, and 9: Development of Highly Potent and Selective CDK4/9 Inhibitors

CDK4/6
inhibitors are effective in treating HR+/HER2− breast cancer but face limitations due to
therapeutic
resistance and hematological toxicity, particularly from strong CDK6
inhibition. To address these challenges, designing selective inhibitors
targeting specific cyclin-dependent kinases (CDK) members could offer
clinical advantages and broaden CDK inhibitor indications. However,
the highly conserved binding pockets of CDKs complicate selective
targeting. This study leverages in silico modeling and structural
analysis of cocrystal data to identify subtle differences in key CDK
binding pockets. Notably, a sequence difference in the αD-helix
motif between CDK4 and CDK6 provides a targetable “sweet spot”
for selectivity. By incorporating a 1,4-trans-cyclohexanediamine side
chain, we designed molecules that favor interactions with CDK4 over
CDK6 and explored potential dual CDK4/9 inhibition. This approach
yielded a lead compound with distinct in vitro selectivity and promising
in vivo pharmacokinetics, offering valuable insights for the development
of selective next-generation CDK inhibitors.