biostudies-literatureZhang XNCI NIH HHS737-746https://www.ebi.ac.uk/biostudies/studies/S-EPMC6592777biostudies-literatureUnknown15(7)Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (for example, SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or proteolysis targeting chimeras, PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16-a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases-as a target of electrophilic PROTACs that promote the nuclear-restricted degradation ofNature chemical biologyElectrophilic PROTACs that degrade nuclear proteins by engaging DCAF16.PMC6592777K00 CA212467R50 CA211526R37 CA087660R35 CA231991Crowley VMDix MMCravatt BFZhang XWucherpfennig TGfalseElectrophilic PROTACs that degrade nuclear proteins by engaging DCAF16.Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (for example, SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or proteolysis targeting chimeras, PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16-a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases-as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of2019-01-01T00:00:00Z2019 Jul2025-04-19T23:41:47.32Z2020-05-21T23:04:45ZS-EPMC65927773120934910.1038/s41589-019-0279-5