Discovery of substituted isoquinolinediones as potent and selective inhibitors of cyclin-dependent kinase 4: 2. Benzylenamine series

4370 Inhibition of cyclin-dependent kinase 4 (CDK4) is predicted to provide an effective therapeutic treatment for cancer. Design and discovery of small molecule inhibitors that are selective for CDK4 have been actively pursued in many laboratories. However, achieving high levels of selectivity for CDK4, versus other CDKs and ATP-dependent kinases, presents a significant challenge. We demonstrate that isoquinolinedione is an attractive scaffold for selective CDK4 inhibitors. Adding a substituted benzylenamine moiety to the scaffold yielded highly potent and selective inhibitors of CDK4. Replacing the phenyl ring of the benzylenamine moiety with a pyridyl ring also generated potent and selective CDK4 inhibitors. Molecular modeling will be presented to demonstrate the key interactions with the CDK4 enzyme. We will also present the synthesis and SAR for the series.