New Paper – Development of CDK inhibitors

RSC Chem. Biol., 2023, 4, 146-164

https://doi.org/10.1039/D2CB00201A

https://pubs.rsc.org/en/content/articlelanding/2023/cb/d2cb00201a

Ian Hope, Jane A. Endicott and Jessica E. Watt*

Cyclin-dependent kinase (CDK) targeted drug discovery strategies have predominantly used biochemical, activity-based assays coupled with structural insight to improve inhibitor potency and selectivity. 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.

There is a wealth of structural information regarding CDK assemblies and inhibitor complexes derived from X-ray crystallographic studies and cryo-electron microscopy, providing insight into the functional roles and regulatory mechanisms of CDKs and their interaction partners.

With an increasing number of protein–protein and allosteric sites being identified through the structural exploration of larger CDK-containing macromolecular complexes, further understanding of protein–protein interfaces and their mechanisms of action can provide new sites to target. Identifying sites necessary for key interactions with protein interaction partners and determining small-molecule binding capabilities via fragment screening may increase selectivity and reduce off-target effects.

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.

Last modified: Thu, 08 Jun 2023 13:43:07 BST