The CDK Inhibitor CR8 Acts as a Molecular Glue Degrader That Depletes Cyclin K

Abstract

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation. Unlike traditional enzyme inhibitors, such molecular glue degraders act sub-stoichiometrically to catalyse rapid depletion of previously inaccessible targets. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Through systematic mining of databases for correlations between the cytotoxicity of 4,518 compounds and E3 ligase expression levels across hundreds of human cancer cell lines, we identified CR8, a cyclin-dependent kinase (CDK) inhibitor, as a compound that acts as a molecular glue degrader. A solvent-exposed pyridyl moiety of CR8, in its CDK-bound form, induces CDK12-cyclin K complex formation with DDB1, the CUL4 adaptor protein, bypassing the requirement for a substrate receptor and presenting cyclin K (cycK) for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy to turn target binders into molecular glues.