Deubiquitinase-targeting chimeras for targeted protein stabilization
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Abstract
Many diseases are driven by proteins that are aberrantly ubiquitinated and degraded. These diseases would be therapeutically benefited by targeted protein stabilization (TPS). Here we present deubiquitinase-targeting chimeras (DUBTACs), heterobifunctional small molecules consisting of a deubiquitinase recruiter linked to a protein-targeting ligand, to stabilize the levels of specific proteins degraded in a ubiquitin-dependent manner. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48-ubiquitin-specific deubiquitinase OTUB1. We showed that a DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR), robustly stabilized ΔF508-CFTR protein levels, leading to improved chloride channel conductance in human cystic fibrosis bronchial epithelial cells. We also demonstrated stabilization of the tumor suppressor kinase WEE1 in hepatoma cells. Our study showcases covalent chemoproteomic approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS.
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NJH-2-057, formed by combining EN523 (a selective OTUB1 binder) with lumacaftor, effectively inhibits ΔF508-CFTR degradation, increases protein levels, and shows improved stabilization compared with lumacaftor alone in cystic fibrosis donor cells.
“This DUBTAC effectively inhibits ΔF508-CFTR degradation, increasing protein levels and demonstrating improved stabilization compared to lumacaftor alone in cystic fibrosis donor cells.548”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [548]
Nomura's team developed deubiquitinase-targeting chimeras (DUBTACs) for targeted protein stabilization, inspired by PROTAC.
“Nomura’s team, inspired by PROTAC, developed deubiquitinase-targeting chimeras (DUBTACs) for TPS.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [548]
A targeted protein stabilization platform called DUBTACs has been developed using a covalent deubiquitinase recruiter.
“a targeted protein stabilization platform, termed deubiquitinase-targeting chimeras (DUBTACs) has been developed using a covalent deubiquitinase recruiter195.”
From Advances in covalent drug discovery (2022) · cites this paper as [195]
Through chemoproteomic data analysis and an ABPP-based screen, a covalent OTUB1 recruiter was discovered that could be incorporated into bifunctional compounds that stabilize mutant CFTR, whose degradation drives cystic fibrosis.
“Through analysis of chemoproteomic data and an ABPP-based screen, a covalent OTUB1 recruiter was discovered that could be incorporated into bifunctional compounds that stabilize mutant cystic fibrosis transmembrane conductance regulator (CFTR), the degradation of which drives cystic fibrosis.”
From Advances in covalent drug discovery (2022) · cites this paper as [195]
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- Authors
- Henning, N. J., Boike, L., Spradlin, J. N., Ward, C. C., Liu, G., Zhang, E., Belcher, B. P., Brittain, S. M., Hesse, M. J., Dovala, D., McGregor, L. M., Valdez Misiolek, R., Plasschaert, L. W., Rowlands, D. J., Wang, F., Frank, A. O., Fuller, D., Estes, A. R., Randal, K. L., Panidapu, A., McKenna, J. M., Tallarico, J. A., Schirle, M., & Nomura, D. K.
- Affiliations
- Innovative Genomics Institute (US)
- Corresponding author
- Nomura, Daniel K.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2022-02-24
- Volume
- 18
- Issue
- 4
- Pages
- 412-421
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC10125259
- OpenAlex
- W4225364558
- Cited by
- 344
- References
- 60
- Citations by year
- 2026: 63 · 2025: 86 · 2024: 74 · 2023: 73 · 2022: 39 · 2021: 8 · 2014: 1
- FWCI
- 22.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis Institutes for BioMedical ResearchMark Foundation for Cancer Research
- National Institutes of HealthMark Foundation for Cancer ResearchNovartis Institutes for BioMedical ResearchNational Science Foundation
- 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
- OTUB1, induced proximity, ΔF508-CFTR, lumacaftor, cystic fibrosis, WEE1, protein degradation
- MeSH terms
- Deubiquitinating Enzymes, Chimera, Cystic Fibrosis, Humans, Ligands, Cystic Fibrosis Transmembrane Conductance Regulator, Ubiquitin
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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