Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications
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Abstract
Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only a few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications.
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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 [189]
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 [189]
Additional generic E3 ligases (RNF4, RNF114, KEAP1, FEM1B) have been shown to be exploitable by PROTACs using small-molecule covalent tools to degrade BRD4.
“a few additional ‘generic’ E3 ligases have been shown to be exploitable by PROTACs, using small-molecule covalent tools that specifically recruit the ligases to degrade the prototypical TPD substrate, BRD4; these ligases include ring finger protein 4 (RNF4)132, RNF114 (refs133–135), KEAP1 (refs136,137) and most recently, fem-1 homologue B (FEM1B)138.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [132]
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 [44]
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- Authors
- Ward, C. C., Kleinman, J. I., Brittain, S. M., Lee, P. S., Chung, C. Y. S., Kim, K., Petri, Y., Thomas, J. R., Tallarico, J. A., McKenna, J. M., Schirle, M., & Nomura, D. K.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Nomura, Daniel K.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-05-06
- Volume
- 14
- Issue
- 11
- Pages
- 2430-2440
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC7422721
- OpenAlex
- W2949862037
- Cited by
- 336
- References
- 48
- Citations by year
- 2026: 40 · 2025: 46 · 2024: 50 · 2023: 45 · 2022: 58 · 2021: 50 · 2020: 33 · 2019: 14
- FWCI
- 12.91
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- ACS Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis
- University of California Berkeley
- National Cancer Institute (F31CA225173)
- 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
- targeted protein degradation, RNF4, chemoproteomics, activity-based protein profiling, RING domain, heterobifunctional degraders, JQ1, BET inhibitors, BRD4 degradation, proteasomal degradation, undruggable proteins
- MeSH terms
- Protein Domains, Bromodomain Containing Proteins, Cysteine, Humans, Ligands, Nuclear Proteins, Protein Binding, Structure-Activity Relationship, Transcription Factors, Zinc, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Small Molecule Libraries, Ubiquitination, Coordination Complexes, Proteolysis, Molecular Docking Simulation
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