DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras

J Am Chem Soc. 2021 Apr 7;143(13):5141-5149. doi: 10.1021/jacs.1c00990.

Xiaoyu Zhang ¹, Lena M Luukkonen ², Christie L Eissler ², Vincent M Crowley ¹, Yu Yamashita ¹ ³, Michael A Schafroth ¹, Shota Kikuchi ², David S Weinstein ², Kent T Symons ², Brian E Nordin ², Joe L Rodriguez ², Thomas G Wucherpfennig ¹, Ludwig G Bauer ¹, Melissa M Dix ¹, Dean Stamos ², Todd M Kinsella ², Gabriel M Simon ², Kristen A Baltgalvis ², Benjamin F Cravatt ¹

Affiliations

1 The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92307, United States.
2 Vividion Therapeutics, 5820 Nancy Ridge Dr, San Diego, California 92121, United States.
3 Medicinal Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kawauchi-cho, Tokushima, 771-0192, Japan.

PMID: 33783207 DOI: 10.1021/jacs.1c00990

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.

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