DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras

Abstract

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.

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

“…15 Finally, FKBPs are the key enabling adaptors for the clinically approved immunosuppressants FK506 and rapamycin as well as for several recently identied molecular glues. [16][17][18][19][20][21][22] Previously, we developed bicyclic [4.3.1] sulfonamides, [23][24][25][26][27] which mimic the core of the natural products FK506 and rapamycin, retain the anti-infective 23 and BMP-stimulating properties 6,10 of these natural products, but lack their immunosuppressive properties. However, the shallow FKBP binding site generally makes the development of ligands with drug-like properties challenging.…”

Piperlongumine (PL) conjugates induce targeted protein degradation

“…Therefore, finding new E3 ligase ligands to expand the toolbox of PROTAC technology is critical for further development of this field. Significant progress has been made in this regard in the last several years, resulting in the discovery of a number of new E3 ligase ligands[4], including some covalent ones that can recruit DCAF11[14], DCAF16[16], KEAP1[17b], RNF114[18], and RNF4[19] E3 ligases for PROTAC designing and protein degradation. Based on mathematical modeling[34] and previous studies[16–17, 18a, 39], covalent E3 ligase ligand-based PROTACs may outperform non-covalent E3 ligase ligand-based PROTACs due to better kinetics of ternary complex formation, and minimal perturbation of its endogenous substrates with low fractional occupancy of the recruited E3 ligase.…”

“…Recent studies have also shown that cancer cells develop resistance to VHL-based bromodomain and extra-terminal domain (BET) PROTACs due to loss of CUL2 and to CRBN-based BET and CDK9 PROTACs because of CRBN loss[12]. Therefore, significant efforts have been devoted to finding new E3 ligase ligands, resulting in the discovery of ligands that can recruit AhR[13], DCAF11[14], DCAF15[15], DCAF16[16], KEAP1[17], RNF114[18], and RNF4[19] E3 ligases to degrade POIs. Identifying more E3 ligase ligands can further expand the toolbox, overcome the drug resistance, and potentially generate more potent and specific PROTACs.…”

Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications

“…Through this screen and using chemoproteomic approaches, they identified a covalent fragment KB02 as a recruiter for the substrate receptor DCAF16 of CUL4-DDB1 E3 ligases for TPD applications 8 . In a fourth successful example, Zhang et al performed a functional screen with a focused library of electrophilic PROTACs to discover a new recruiter that targets cysteines on DCAF11 9 . Thus, these studies have collectively showcased the utility of chemoproteomic approaches and cysteine-targeting ligands to expand the arsenal of E3 ligase recruiters for TPD applications.…”