Discovery and Optimization of Highly Selective Inhibitors of CDK5

Autosomal
dominant polycystic kidney disease (ADPKD) is the most
prevalent monogenic human disease, but to date, only one therapy (tolvaptan)
is approved to treat kidney cysts in ADPKD patients. Cyclin-dependent
kinase 5 (CDK5), an atypical member of the cyclin-dependent kinase
family, has been implicated as a target for treating ADPKD. However,
no compounds have been disclosed to date that selectively inhibit
CDK5 while sparing the broader CDK family members. Herein, we report
the discovery of CDK5 inhibitors, including GFB-12811, that are highly selective over the other tested kinases. In cellular
assays, our compounds demonstrate CDK5 target engagement while avoiding
anti-proliferative effects associated with inhibiting other CDKs.
In addition, we show that the compounds in this series exhibit promising in vivo PK profiles, enabling their use as tool compounds
for interrogating the role of CDK5 in ADPKD and other diseases.