Abstract 2025 The Glue Gimmick - Crystallization of CRBN + Neosubstrate + Molecular Glue Ternary Complexes to Improve Molecular Glue Specificity

Molecular glues (MGs) are cereblon (CRBN)-binding molecules that induce targeted degradation of a neosubstrate, a protein that binds to CRBN only in the context of a MG. Currently, thalidomide, pomalidomide, and lenalidomide are the only FDA-approved MGs used to treat multiple myeloma (MM) and myelodysplastic syndrome (MDS). These MGs, however, are non-selective, leading to off-target effects, reduced efficacy, and increased toxicity in patients. Our goal is to improve the selectivity of existing MGs by identifying residues of CRBN and neosubstrate that form a direct interaction with the MG at the binding interface using crystallography.