biostudies-literatureZhang XNational Cancer InstituteNCI NIH HHSDamon Runyon Cancer Research Foundation5141-5149https://www.ebi.ac.uk/biostudies/studies/S-EPMC8309050biostudies-literatureUnknown143(13)Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.Journal of the American Chemical SocietyDCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras.PMC8309050CA212467K99 CA248715CA231991K00 CA212467DRG-2341-18F99 CA212467CA248715R35 CA231991Crowley VMKikuchi SRodriguez JLDix MMCravatt BFNordin BEEissler CLWucherpfennig TGBauer LGBaltgalvis KASchafroth MASymons KTSimon GMYamashita YZhang XWeinstein DSKinsella TMLuukkonen LMStamos DfalseDCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras.Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.2021-01-01T00:00:00Z2021 Apr2026-05-31T07:12:55.841Z2025-04-04T07:55:57.144ZS-EPMC83090503378320710.1021/jacs.1c00990