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

SUBMITTER: Geng Q 

PROVIDER: S-EPMC12861308 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature