{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Nuffield Department of Medicine, Centre for Medicines Discovery, Target Discovery Institute, University of Oxford, Oxford, UK",
    "Nuffield Department of Medicine, CAMS Oxford Institute and Centre for Medicines Discovery, University of Oxford, Oxford, UK",
    "Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK",
    "Hit Discovery and Optimization (HDO) Pfizer Inc, Groton, CT USA",
    "Present Address: Department of Microbiology, Harvard Medical School, Boston, MA USA",
    "Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK",
    "Discovery Biology and Pharmacology, Pfizer Inc, Groton, CT USA",
    "Department of Biochemistry, University of Oxford, Oxford, UK",
    "Cancer Research Horizons, Francis Crick Institute, London, UK",
    "Centre for Chemical Biology, Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 30,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hannah B. L. Jones"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Simeon D. Draganov"
    },
    {
      "affs": [
        2
      ],
      "name": "Sofia Schönbauer Huamán"
    },
    {
      "affs": [
        1
      ],
      "name": "Peter A. C. Wing",
      "orcid": "0000-0002-2354-3281"
    },
    {
      "affs": [
        3
      ],
      "name": "Chuong Nguyen"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Zhu Liang"
    },
    {
      "affs": [
        2
      ],
      "name": "Julia Dörner"
    },
    {
      "affs": [
        2
      ],
      "name": "Jasper Lithgow"
    },
    {
      "affs": [
        0
      ],
      "name": "Emma Murphy"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Alice Beard"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Angela Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Andrea Pierangelini",
      "orcid": "0009-0009-9396-619X"
    },
    {
      "affs": [
        5
      ],
      "name": "Jack W. Houghton"
    },
    {
      "affs": [
        6
      ],
      "name": "Mackenzie E. Robert"
    },
    {
      "affs": [
        0
      ],
      "name": "Sarah Flannery"
    },
    {
      "affs": [
        7
      ],
      "name": "Cara J. Ellison"
    },
    {
      "affs": [
        2
      ],
      "name": "Sakshi Sharma"
    },
    {
      "affs": [
        2
      ],
      "name": "Anthony Tumber"
    },
    {
      "affs": [
        0
      ],
      "name": "Lynn Wambua"
    },
    {
      "affs": [
        0
      ],
      "name": "Iolanda Vendrell"
    },
    {
      "affs": [
        5
      ],
      "name": "Edward W. Tate"
    },
    {
      "affs": [
        7
      ],
      "name": "Paul R. Elliott",
      "orcid": "0000-0002-7641-2103"
    },
    {
      "affs": [
        3
      ],
      "name": "Graham M. West"
    },
    {
      "affs": [
        0
      ],
      "name": "Darragh P. O’Brien"
    },
    {
      "affs": [
        2
      ],
      "name": "Eidarus Salah"
    },
    {
      "affs": [
        8
      ],
      "name": "Andrew P. Turnbull"
    },
    {
      "affs": [
        2
      ],
      "name": "Christopher J. Schofield"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Benedikt M. Kessler",
      "orcid": "0000-0002-8160-2446"
    },
    {
      "affs": [
        2,
        9
      ],
      "name": "Lennart Brewitz"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Adán Pinto-Fernández",
      "orcid": "0000-0003-1693-9664"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7x7ws5mn7mnd8.bib",
  "cited_by": 0,
  "doi": "10.1038/s44386-026-00092-z",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710844/",
  "id": "7x7ws5mn7mnd8",
  "issns": [
    "3005-1452"
  ],
  "landing_url": "https://doi.org/10.1038/s44386-026-00092-z",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Ubiquitin and proteasome pathways"
    ]
  ],
  "openalex": "W7223669882",
  "pdf_url": "https://www.nature.com/articles/s44386-026-00092-z.pdf",
  "pmcid": "PMC13710844",
  "pmid": "42934303",
  "published": "2026-10-26",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/7x7ws5mn7mnd8.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:43Z",
      "native_id": "PMC13710844",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s44386-026-00092-z"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Ubiquitin and proteasome pathways",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity",
  "title_text": "Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:43Z",
  "url": "https://research.draconitic.com/paper/7x7ws5mn7mnd8",
  "venue": "npj Drug Discovery",
  "versions": []
}