Development of Potent and Selective CK1α Molecular Glue Degraders

Abstract

Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin ligase, thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce casein kinase 1 alpha (CK1α) degradation. By scaffold hopping and rational modification of the chemical scaffold, we identified an imidazo[1,2-a]pyrimidine compound that induces potent and selective CK1α degradation. A structure–activity relationship study of the lead compound, QXG-6442, identified the chemical features that contribute to degradation potency and selectivity compared to other frequently observed neosubstrates. The glutarimide library screening and structure–activity relationship medicinal chemistry approach we employed is generally useful for developing new molecular glue degraders toward new targets of interest.