Direct-to-Biology Enabled Molecular Glue Discovery.

ABSTRACT: Molecular glues powerfully control protein proximity but have largely eluded direct screening. A promising avenue for addressing this challenge lies within pinpointing the fundamental features for function-first identification of molecular gluing events. In the widely accepted mechanism, a molecular glue stabilizes two proteins within a ternary complex─here, we show how differences in affinity for ternary and binary complexes directly categorize glues from nonglues. We leverage these differences together with high-throughput chemical synthesis and affinity-selection mass-spectrometry to discover a molecular glue from a suite of over 20,000 crude chemical reaction mixtures. Orthogonal assays robustly support the identification of molecular glues via ternary complex stability. Our findings s

SUBMITTER: Hu M 

PROVIDER: S-EPMC12814336 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature