Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice

Although cyclin-dependent kinase 2 (CDK2) is a validated
target
for both cancer and contraception, developing a CDK2 inhibitor with
exquisite selectivity has been challenging due to the structural similarity
of the ATP-binding site, where most kinase inhibitors bind. We previously
discovered an allosteric pocket in CDK2 with the potential to bind
a selective compound and then discovered and structurally confirmed
an anthranilic acid scaffold that binds this pocket with high affinity.
These allosteric inhibitors are selective for CDK2 over structurally
similar CDK1 and show contraceptive potential. Herein, we describe
the screening and optimization that led to compounds like EF-4-177 with nanomolar affinity for CDK2. EF-4-177 is metabolically
stable, orally bioavailable, and significantly disrupts spermatogenesis,
demonstrating this series’ therapeutic potential. This work
details the discovery of the highest affinity allosteric CDK inhibitors
reported and shows promise for this series to yield an efficacious
and selective allosteric CDK2 inhibitor.