{
  "abstract": "ClpP protease maintains proteostasis in human mitochondria and is overexpressed in cancers such as acute myeloid leukemia (AML). While activators such as dordaviprone (ONC201) have reached the clinic, the development of ClpP inhibitors has been hampered by paradoxical activation upon orthosteric inhibitor binding. Here, we report a series of quinazolinone-based compounds that allosterically inhibit human ClpP with nanomolar potency. Cryo-EM and H/D exchange mass spectrometry reveal that our lead compound binds sub-stoichiometrically to a distal hydrophobic pocket ~30 Å from the active sites, disrupts a conserved inter-subunit cluster, and induces a conformational change that misaligns the catalytic triad, thereby inactivating ClpP. The binding site of our quinazolinone-based inhibitors partially overlaps with that of the activator dordaviprone. In a xenograft mouse model of leukemia, our lead compound significantly reduced tumor burden following short-term oral administration. Our findings identify a regulatory hotspot in human ClpP and a mechanistically distinct inhibition strategy.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON Canada",
    "Department of Anatomy and Cell Biology, McGill University, Montréal, QC Canada",
    "Ontario Institute for Cancer Research, Toronto, ON Canada",
    "Princess Margaret Cancer Centre, University Health Network, Toronto, ON Canada",
    "Department of Chemistry, University of Toronto, Toronto, ON Canada",
    "UHN Therapeutics, Krembil Brain Institute, University Health Network, Toronto, ON Canada",
    "Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON Canada",
    "Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON Canada",
    "Centre de Recherche en Biologie Structurale (CRBS), Montréal, QC Canada"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 35,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Monica M. Goncalves",
      "orcid": "0009-0001-2447-146X"
    },
    {
      "affs": [
        1
      ],
      "name": "Adwaith B. Uday",
      "orcid": "0009-0005-1524-6307"
    },
    {
      "affs": [
        2
      ],
      "name": "Iain D. G. Watson",
      "orcid": "0000-0003-3508-3240"
    },
    {
      "affs": [
        2
      ],
      "name": "Anh M. Chau",
      "orcid": "0009-0004-4569-0604"
    },
    {
      "affs": [
        2
      ],
      "name": "Shiva Kalhor-Monfared"
    },
    {
      "affs": [
        2
      ],
      "name": "Benson Wan",
      "orcid": "0009-0004-6689-0867"
    },
    {
      "affs": [
        2
      ],
      "name": "Taira Kiyota",
      "orcid": "0000-0001-6313-3482"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Quinn W. Currie"
    },
    {
      "affs": [
        3
      ],
      "name": "Yulia Jitkova"
    },
    {
      "affs": [
        3
      ],
      "name": "Yue Feng",
      "orcid": "0009-0002-9697-1903"
    },
    {
      "affs": [
        4
      ],
      "name": "Matthew Diamandas"
    },
    {
      "affs": [
        3
      ],
      "name": "Dakai Ling"
    },
    {
      "affs": [
        3
      ],
      "name": "Mary Ma"
    },
    {
      "affs": [
        5
      ],
      "name": "Ross S. Mancini",
      "orcid": "0009-0004-8821-2565"
    },
    {
      "affs": [
        2
      ],
      "name": "Zhezhou Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Matias Casás-Selves"
    },
    {
      "affs": [
        2
      ],
      "name": "Dhananjay Joshi"
    },
    {
      "affs": [
        2
      ],
      "name": "Mohammed Mohammed"
    },
    {
      "affs": [
        2
      ],
      "name": "Ratheesh Subramaniam"
    },
    {
      "affs": [
        2
      ],
      "name": "Evelyne Lima Fernandes"
    },
    {
      "affs": [
        3
      ],
      "name": "Yongran Yan",
      "orcid": "0009-0005-7337-4331"
    },
    {
      "affs": [
        3
      ],
      "name": "Neil Pomroy",
      "orcid": "0009-0009-1921-1709"
    },
    {
      "affs": [
        3
      ],
      "name": "Rose Hurren"
    },
    {
      "affs": [
        3
      ],
      "name": "Marcela Gronda"
    },
    {
      "affs": [
        0
      ],
      "name": "Algirdas Velyvis"
    },
    {
      "affs": [
        4
      ],
      "name": "Andrei K. Yudin",
      "orcid": "0000-0003-3170-9103"
    },
    {
      "affs": [
        4,
        5,
        6
      ],
      "name": "Mark A. Reed"
    },
    {
      "affs": [
        3
      ],
      "name": "Gil Prive"
    },
    {
      "affs": [
        2,
        7
      ],
      "name": "Ahmed Aman",
      "orcid": "0000-0002-0275-205X"
    },
    {
      "affs": [
        2
      ],
      "name": "Methvin Isaac"
    },
    {
      "affs": [
        2
      ],
      "name": "Richard Marcellus"
    },
    {
      "affs": [
        2
      ],
      "name": "David Uehling"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Aaron D. Schimmer",
      "orcid": "0000-0003-4023-3899"
    },
    {
      "affs": [
        1,
        8
      ],
      "name": "Natalie Zeytuni",
      "orcid": "0000-0002-5708-4095"
    },
    {
      "affs": [
        0
      ],
      "name": "Siavash Vahidi",
      "orcid": "0000-0001-8637-3710"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/32btqjkexq4m5.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-78140-5",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13714246/",
  "id": "32btqjkexq4m5",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-78140-5",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Heat shock proteins research"
    ]
  ],
  "openalex": "W7214585551",
  "pdf_url": "https://www.nature.com/articles/s41467-026-78140-5_reference.pdf",
  "pmcid": "PMC13714246",
  "pmid": "42946762",
  "published": "2026-09-28",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/32btqjkexq4m5.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:21:47Z",
      "native_id": "PMC13714246",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41467-026-78140-5"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Heat shock proteins research",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Allosteric inhibition of human mitochondrial ClpP by hijacking the dordaviprone (ONC201) binding site",
  "title_text": "Allosteric inhibition of human mitochondrial ClpP by hijacking the dordaviprone (ONC201) binding site",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:47Z",
  "url": "https://research.draconitic.com/paper/32btqjkexq4m5",
  "venue": "Nature Communications",
  "versions": []
}