The contribution of cyclic imide stereoisomers on cereblon-dependent activity.

ABSTRACT: Thalidomide, lenalidomide, and their derivatives mimic glutarimide and aspartimide protein modifications that give rise to a motif recognized by the E3 ligase substrate adapter cereblon (CRBN). These cyclic imides have a chiral center that, given the biological significance of chirality, may influence CRBN's function and therapeutic applications. Here, we systematically examine cyclic imides in small molecules, peptides, and proteins to assess their racemization, CRBN engagement, ternary complex formation in vitro, and resulting degradation outcomes in cells. While the thalidomide-binding domain of CRBN consistently favors the (S)-stereoisomer across all cyclic imide small molecule ligands and engineered proteins, we find that, in some cases, the (R)-stereoisomer can b

SUBMITTER: Amako Y 

PROVIDER: S-EPMC12117711 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature