Discovery of Novel -(5-(Pyridin-3-yl)-1-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors' potency and selectivity. The representative compound potently inhibited CDK7 with an IC value of 4 nM and showed high selectivity over CDKs. Compound showed high potency to inhibit cyst growth and exhibited lower cytotoxicity than THZ1 in an Madin-Darby canine kidney cyst model. In addition, compound was also highly efficacious in suppressing renal cyst development in an embryonic kidney cyst model and ADPKD mouse model. These results indicate that compound represents a promising lead compound that deserves further investigation to discover novel therapeutic agents for ADPKD.