Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity
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.
Authors
- Edward W. Tate (ORCID: https://orcid.org/0000-0003-2213-5814)
- Sarah E. Flannery (ORCID: https://orcid.org/0000-0002-6580-5665)
- Graham M. West (ORCID: https://orcid.org/0000-0003-2157-2123)
- Peter A. C. Wing (ORCID: https://orcid.org/0000-0002-2354-3281)
- Darragh Patrick O'Brien (ORCID: https://orcid.org/0000-0003-4924-7795)
- Chuong Nguyen (ORCID: https://orcid.org/0000-0001-8373-981X)
- Benedikt Mathias Kessler (ORCID: https://orcid.org/0000-0002-8160-2446)
- Cara J. Ellison (ORCID: https://orcid.org/0000-0003-3483-6896)
- Adán Pinto-Fernández (ORCID: https://orcid.org/0000-0003-1693-9664)
- Iolanda Vendrell (ORCID: https://orcid.org/0000-0001-7187-4061)
- Alice Beard
- Anthony Tumber (ORCID: https://orcid.org/0000-0003-1958-8353)
- Lennart Brewitz (ORCID: https://orcid.org/0000-0002-9465-777X)
- E. Salah (ORCID: https://orcid.org/0000-0001-7552-4966)
- Paul Elliott (ORCID: https://orcid.org/0000-0002-7511-5684)
- Hannah B. L. Jones (ORCID: https://orcid.org/0000-0002-7834-0625)
- A Chen (ORCID: https://orcid.org/0000-0001-7508-7188)
- Jack W. Houghton (ORCID: https://orcid.org/0000-0002-2971-0271)
- Mackenzie E. Robert
- A.P. Turnbull (ORCID: https://orcid.org/0000-0001-6545-4108)
- Lynn Wambua (ORCID: https://orcid.org/0000-0002-6218-199X)
- Simeon D. Draganov (ORCID: https://orcid.org/0000-0002-8695-3499)
- Sofia Schönbauer Huamán
- Julia Dörner
- Andrea Pierangelini (ORCID: https://orcid.org/0009-0009-9396-619X)
- Sakshi Sharma (ORCID: https://orcid.org/0009-0004-2407-583X)
- Zhu Liang (ORCID: https://orcid.org/0000-0001-8223-5003)
- Christopher J. Schofield
- Jasper Lithgow
- Emma Murphy
Institutions
- Harvard University (US)
- Pfizer (United States) (US)
- Discovery Centre (CA)
- The Francis Crick Institute (GB)
- University of Oxford (GB)
- Cancer Research Horizons (GB)
- Institute of Physical Chemistry (PL)
- Imperial College London (GB)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- npj Drug Discovery.
- Published
- 2026-10-26
- DOI
- https://doi.org/10.1038/s44386-026-00092-z
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bristol-Myers Squibb
- Boehringer Ingelheim
- Cancer Research UK
- Chinese Academy of Medical Sciences
- Ono Pharmaceutical
- Pfizer’s Centers for Therapeutic Innovation