DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras
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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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Since 2019, covalent recruiters have been used to validate a large proportion of E3 ligases harnessed for targeted protein degradation, including RNF114, RNF4, DCAF16, DCAF11, KEAP1 and FEM1B.
“Since 2019, covalent recruiters have been used to validate a large proportion of the E3 ligases that have been harnessed for targeted protein degradation, including RING finger protein 114 (RNF114), RNF4, DDB1 and CUL4-associated factor 16 (DCAF16), DCAF11, KEAP1 and, most recently, fem-1 homologue B (FEM1B)187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [191]
Covalent drug discovery platforms have facilitated expansion of targeted protein degradation by enabling discovery of covalent recruiters against E3 ubiquitin ligases.
“Covalent drug discovery platforms have facilitated the expansion of targeted protein degradation approaches by enabling the discovery of covalent recruiters against E3 ubiquitin ligases14,187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [191]
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Targeted Protein Degradation: The New Frontier of Antimicrobial Discovery?
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- Authors
- Zhang, X., Luukkonen, L. M., Eissler, C. L., Crowley, V. M., Yamashita, Y., Schafroth, M. A., Kikuchi, S., Weinstein, D. S., Symons, K. T., Nordin, B. E., Rodriguez, J. L., Wucherpfennig, T. G., Bauer, L. G., Dix, M. M., Stamos, D., Kinsella, T. M., Simon, G. M., Baltgalvis, K. A., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Vividion Therapeutics (United States) (US)
- Otsuka (Japan) (JP)
- Corresponding author
- Zhang, Xiaoyu
- Cravatt, Benjamin F.
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-03-30
- Volume
- 143
- Issue
- 13
- Pages
- 5141-5149
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC8309050
- OpenAlex
- W3152373163
- Cited by
- 199
- References
- 36
- Citations by year
- 2026: 37 · 2025: 41 · 2024: 51 · 2023: 30 · 2022: 32 · 2021: 8
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA212467, CA231991, CA248715)
- Damon Runyon Cancer Research Foundation (DRG-2341-18)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, E3 ubiquitin ligase, ubiquitin-proteasome system, cysteine modification, FBXW7, androgen receptor, prostate cancer, bifunctional molecules, functional screening
- MeSH terms
- Humans, Male, Prostatic Neoplasms, Receptors, Androgen, Ubiquitin, Ubiquitin-Protein Ligase Complexes, Cell Line, Tumor, Proteasome Endopeptidase Complex, Proteolysis
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