Emerging approaches to CDK inhibitor development, a structural perspective

Abstract

Aberrant activity of the cyclin-dependent kinase family is frequently noted in a number of diseases identifying them as potential targets for drug development. However, current CDK inhibitors lack specificity owing to the high sequence and structural conservation of the ATP binding cleft across family members, highlighting the necessity of finding novel modes of CDK inhibition. The wealth of structural information regarding CDK assemblies and inhibitor complexes derived from X-ray crystallographic studies has been recently complemented through the use of cryo-electron microscopy. These recent advances have provided insights into the functional roles and regulatory mechanisms of CDKs and their interaction partners. This review explores the conformational malleability of the CDK subunit, the importance of SLiM recognition sites in CDK complexes, the progress made in chemically induced CDK degradation and how these studies can contribute to CDK inhibitor design. Additionally, fragment-based drug discovery can be utilised to identify small molecules that bind to allosteric sites on the CDK surface employing interactions which mimic those of native protein–protein interactions. These recent structural advances in CDK inhibitor mechanisms and in chemical probes which do not occupy the orthosteric ATP binding site can provide important insights for targeted CDK therapies.