Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.

ABSTRACT: Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics^1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs^4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue

SUBMITTER: Li YD 

PROVIDER: S-EPMC9949066 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature