Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
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Abstract
Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (for example, SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or proteolysis targeting chimeras, PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16-a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases-as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of proteins. We find that only a modest fraction (~10-40%) of DCAF16 needs to be modified to support protein degradation, pointing to the potential for electrophilic PROTACs to induce neosubstrate degradation without substantially perturbing the function of the participating E3 ligase.
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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 [190]
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 [190]
A nuclear E3 ligase, DCAF16, has been shown to restrict target degradation to the nucleus.
“a nuclear E3 ligase, DCAF16, has been shown to restrict target degradation to the nucleus131.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [131]
A PROTAC that targets nuclear FKBP12 for degradation by engaging DCAF16 has been reported.
“a PROTAC that targets nuclear FKBP12 for degradation by engaging DCAF16 has been reported [70].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [70]
Covalent binding to E3 ligases is acceptable for PROTACs.
“While covalent binding to E3 ligases is acceptable 31,44 ,”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [31]
The expression profile of the chosen E3 ligase can be exploited to degrade a target in specific tissues or cellular compartments.
“The expression profile of the chosen E3 ligase can also be exploited to degrade a target in specific tissues or cellular compartments 31 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [31]
A PROTAC induces degradation of non-native substrates via cysteine-directed covalent recruitment of DCAF16.
“More recently, a PROTAC was shown to induce the degradation of non-native substrates via cysteine-directed covalent recruitment of DCAF16 (ref. 31 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [31]
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Fragment-based covalent ligand discovery
Lu, W., Kostic, M., Zhang, T., Che, J., Patricelli, M. P., Jones, L. H., Chouchani, E. T., & Gray, N. S. (2021) · RSC Chemical Biology · doi:10.1039/d0cb00222d · Cited by 136 · see citing works
Ligandability of E3 Ligases for Targeted Protein Degradation Applications
Belcher, B. P., Ward, C. C., & Nomura, D. K. (2023) · Biochemistry · doi:10.1021/acs.biochem.1c00464 · Cited by 132 · see citing works
Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00924-z · Cited by 126 · see citing works
Self-citationA Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Tong, B., Spradlin, J. N., Novaes, L. F. T., Zhang, E., Hu, X., Moeller, M., Brittain, S. M., McGregor, L. M., McKenna, J. M., Tallarico, J. A., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00348 · Cited by 118 · see citing works
Bifunctional chemical probes inducing protein–protein interactions
Maniaci, C., & Ciulli, A. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.07.003 · Cited by 100 · see citing works
PROTAC degraders as chemical probes for studying target biology and target validation
Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98 · see citing works
PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network
Reichermeier, K. M., Straube, R., Reitsma, J. M., Sweredoski, M. J., Rose, C. M., Moradian, A., den Besten, W., Hinkle, T., Verschueren, E., Petzold, G., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.013 · Cited by 78 · see citing works
Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries
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A critical evaluation of the approaches to targeted protein degradation for drug discovery
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Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence
Duran-Frigola, M., Cigler, M., & Winter, G. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11098 · Cited by 50 · see citing works
Identification and characterization of cancer vulnerabilities via targeted protein degradation
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Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms
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Pinch, B. J., Buckley, D. L., Gleim, S., Brittain, S. M., Tandeske, L., D'Alessandro, P. L., Hauseman, Z. J., Lipps, J., Xu, L., Harvey, E. P., et al. (2022) · Cell Chemical Biology · doi:10.1016/j.chembiol.2021.08.007 · Cited by 20 · see citing works
Targeted protein modification as a paradigm shift in drug discovery
Amirian, R., Azadi Badrbani, M., Izadi, Z., Samadian, H., Bahrami, G., Sarvari, S., Abdolmaleki, S., Nabavi, S. M., Derakhshankhah, H., & Jaymand, M. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115765 · Cited by 18 · see citing works
Adhikari, B., Schneider, K., Diebold, M., Sotriffer, C., & Wolf, E. (2024) · eLife · doi:10.7554/elife.98450.3 · Cited by 6 · see citing works
- Authors
- Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Zhang, Xiaoyu
- Cravatt, Benjamin F.
- Venue
- Nature Chemical Biology
- Published
- 2019-06-17
- Volume
- 15
- Issue
- 7
- Pages
- 737-746
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6592777
- OpenAlex
- W2949485830
- Cited by
- 487
- References
- 51
- Citations by year
- 2026: 59 · 2025: 70 · 2024: 95 · 2023: 56 · 2022: 76 · 2021: 64 · 2020: 45 · 2019: 22
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA212467, CA087660)
- National Cancer Institute (R50CA211526, K00CA212467, F99CA212467, R37CA087660, R01CA087660, R35CA231991)
- 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, chemoproteomics
- MeSH terms
- Dose-Response Relationship, Drug, Humans, Ligands, Nuclear Proteins, Structure-Activity Relationship, Molecular Structure, Protein Kinase Inhibitors, HEK293 Cells, Proteolysis
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