DCAF11 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.

Automated summary

Ligand-induced protein degradation through electrophilic PROTACs has been shown to degrade proteins in human cells by engaging specific cysteines in the poorly characterized E3 ligase substrate adaptor DCAF11. These findings suggest DCAF11 as a potential E3 ligase for ligand-induced protein degradation via electrophilic PROTACs, providing new insights for the development of targeted protein degradation compounds.