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Molecular glue degraders are small, drug-like compounds that induce interactions between an E3 ubiquitin ligase and a target, leading to target ubiquitination and subsequent degradation by the proteasome. Unlike traditional enzyme inhibitors, degraders can act sub-stoichiometrically to catalyse the rapid depletion of previously inaccessible targets. Despite the clinical success of this modality, only two molecular glue degrader classes, thalidomide analogues and aryl sulphonamides, have been well-described thus far and molecular glue discovery remains largely serendipitous. Hence, novel molecular glue degrader examples, as well as methods for their prospective discovery and rational design are highly sought-after. In this work, a systematic search for molecular glue degraders was performed through bioinformatic mining of drug cytotoxicity data for correlations with E3 ligase component expression levels across hundreds of human cancer cell lines. This led to the identification of CR8, a preclinical cyclin-dependent kinase (CDK) inhibitor, as a molecular glue degrader of cyclin K. CR8 was found to facilitate the formation of a complex between CDK12–cyclin K and the CUL4 adaptor protein DDB1, thereby bypassing a canonical substrate receptor and directly presenting cyclin K for ubiquitination and degradation. A solvent-exposed pyridyl moiety of the compound, one that is absent in related inhibitors, protrudes from the kinase pocket and engages DDB1, which suggests more broadly that chemical modification of surface-exposed moieties can confer gain of function glue properties to an inhibitor. Notably, several structurally distinct cyclin K …