Peer-reviewedCC BY 4.0npj Drug Discovery
Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity
10 affiliations
- 1Nuffield Department of Medicine, Centre for Medicines Discovery, Target Discovery Institute, University of Oxford, Oxford, UK
- 2Nuffield Department of Medicine, CAMS Oxford Institute and Centre for Medicines Discovery, University of Oxford, Oxford, UK
- 3Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK
- 4Hit Discovery and Optimization (HDO) Pfizer Inc, Groton, CT USA
- 5Present Address: Department of Microbiology, Harvard Medical School, Boston, MA USA
- 6Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK
- 7Discovery Biology and Pharmacology, Pfizer Inc, Groton, CT USA
- 8Department of Biochemistry, University of Oxford, Oxford, UK
- 9Cancer Research Horizons, Francis Crick Institute, London, UK
- 10Centre for Chemical Biology, Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland
Abstract
Deubiquitinases (DUBs) play key roles in human pathologies, including cancer, infectious, autoimmune, and neurodegenerative diseases. The progress of potent and selective active site-targeting DUB inhibitors into clinical trials has demonstrated the therapeutic opportunities of such molecules; however, the shared catalytic geometry among DUB family members poses a challenge for achieving inhibitor selectivity. We describe a high-throughput, DUB-focused, activity-based proteomics workflow to identify new types of cysteine-reactive DUB inhibitors. We demonstrate the potential of αβ,α′β′-diepoxyketones (DEKs) and ubiquitin-derived covalently reacting alkynes as the first selective, cell-active compounds targeting USP47, OTUD7B (Cezanne), and USP5. These DUBs are reported to have critical roles in inflammasome formation, hypoxia, and viral replication, respectively. The identified compounds phenocopy these findings, demonstrating the tractability of these DUBs as immunotherapeutic targets.
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BibTeX
@article{jones2026activitybased,
title = {{Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity}},
author = {Hannah B. L. Jones and Simeon D. Draganov and Sofia Schönbauer Huamán and Peter A. C. Wing and Chuong Nguyen and Zhu Liang and Julia Dörner and Jasper Lithgow and Emma Murphy and Alice Beard and Angela Chen and Andrea Pierangelini and Jack W. Houghton and Mackenzie E. Robert and Sarah Flannery and Cara J. Ellison and Sakshi Sharma and Anthony Tumber and Lynn Wambua and Iolanda Vendrell and Edward W. Tate and Paul R. Elliott and Graham M. West and Darragh P. O’Brien and Eidarus Salah and Andrew P. Turnbull and Christopher J. Schofield and Benedikt M. Kessler and Lennart Brewitz and Adán Pinto-Fernández},
journal = {npj Drug Discovery},
year = {2026},
month = oct,
doi = {10.1038/s44386-026-00092-z},
url = {https://doi.org/10.1038/s44386-026-00092-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity
AU - Hannah B. L. Jones
AU - Simeon D. Draganov
AU - Sofia Schönbauer Huamán
AU - Peter A. C. Wing
AU - Chuong Nguyen
AU - Zhu Liang
AU - Julia Dörner
AU - Jasper Lithgow
AU - Emma Murphy
AU - Alice Beard
AU - Angela Chen
AU - Andrea Pierangelini
AU - Jack W. Houghton
AU - Mackenzie E. Robert
AU - Sarah Flannery
AU - Cara J. Ellison
AU - Sakshi Sharma
AU - Anthony Tumber
AU - Lynn Wambua
AU - Iolanda Vendrell
AU - Edward W. Tate
AU - Paul R. Elliott
AU - Graham M. West
AU - Darragh P. O’Brien
AU - Eidarus Salah
AU - Andrew P. Turnbull
AU - Christopher J. Schofield
AU - Benedikt M. Kessler
AU - Lennart Brewitz
AU - Adán Pinto-Fernández
PY - 2026
DA - 2026/10/26
JO - npj Drug Discovery
DO - 10.1038/s44386-026-00092-z
UR - https://doi.org/10.1038/s44386-026-00092-z
AB - Deubiquitinases (DUBs) play key roles in human pathologies, including cancer, infectious, autoimmune, and neurodegenerative diseases. The progress of potent and selective active site-targeting DUB inhibitors into clinical trials has demonstrated the therapeutic opportunities of such molecules; however, the shared catalytic geometry among DUB family members poses a challenge for achieving inhibitor selectivity. We describe a high-throughput, DUB-focused, activity-based proteomics workflow to identify new types of cysteine-reactive DUB inhibitors. We demonstrate the potential of αβ,α′β′-diepoxyketones (DEKs) and ubiquitin-derived covalently reacting alkynes as the first selective, cell-active compounds targeting USP47, OTUD7B (Cezanne), and USP5. These DUBs are reported to have critical roles in inflammasome formation, hypoxia, and viral replication, respectively. The identified compounds phenocopy these findings, demonstrating the tractability of these DUBs as immunotherapeutic targets.
SN - 3005-1452
ER -