biostudies-literatureUnknownLi YDNCI NIH HHSSmall 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 <i>trans</i>-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue bioRxiv : the preprint server for biology2023.02.14.528208https://www.ebi.ac.uk/biostudies/studies/S-EPMC9949066biostudies-literatureTemplate-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.PMC9949066K00 CA253754Lumpkin RQi JPark PMCJin CYWang MYEbert BLSlabicki MPuvar KZou CHunkeler MYoon HFicarro SBSandoval BHassan MMFischer ESMarto JATeng MSigua LHTavares ILi YDTsai JMGray NSMajewski FCNowak RPDonovan KAXu SGroendyke BJMa MWfalseTemplate-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.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 <i>trans</i>-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue 2023-01-01T00:00:00Z2023 Feb2025-04-04T11:26:47.349Z2025-04-04T11:26:47.349ZS-EPMC99490663682485610.1101/2023.02.14.528208