{
  "abstract": "The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a class of base-exchange inhibitors (BEXi) targeting human SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades. The sterile alpha and TIR motif containing 1 (SARM1) is a crucial enzyme in axonal degeneration, making it a potential target for treating nervous system diseases. Here, the authors identify and optimize base-exchange inhibitors (BEXi) targeting SARM1, revealing their limitations and highlighting the complexity of SARM1 as a therapeutic target.",
  "abstract_shown": true,
  "affiliations": [
    "Assays, Profiling & Cell Sciences, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. thomas.lundback@astrazeneca.com",
    "AstraZeneca",
    "Assays, Profiling & Cell Sciences, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden",
    "Neuroscience, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK",
    "Protein Sciences, Structural Biology, and Biophysics, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK",
    "Protein Sciences, Structural Biology, and Biophysics, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden",
    "Centre for Genomics Research, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden",
    "Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK",
    "Compound Synthesis & Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden",
    "Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden",
    "Spatial & Quantitative Omics, Discovery Bioanalysis, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK",
    "Neuroscience, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, USA",
    "Neuroscience, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK. rebecca.jarvis@astrazeneca.com"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 36,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Thomas Lundbäck",
      "orcid": "0000-0002-8145-7808"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Vijay Chandrasekar",
      "orcid": "0000-0002-5452-5107"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Chendi Gu"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Hyoungseok Ju",
      "orcid": "0000-0002-6730-2260"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Robyn L. McAdam"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Maria Palomero"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Kasim Sader",
      "orcid": "0000-0002-8517-5410"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Bradley Peter",
      "orcid": "0000-0003-0885-3131"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Lisa Wissler",
      "orcid": "0000-0002-8152-8522"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Philip Nevin",
      "orcid": "0000-0003-4891-7793"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Edmund Foster",
      "orcid": "0000-0002-9284-3229"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Tanguy Jamier",
      "orcid": "0000-0003-3014-3662"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Pravallika Manjappa",
      "orcid": "0000-0002-6753-8492"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Carina A. Johansson",
      "orcid": "0000-0003-3388-831X"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Jenny Sandmark",
      "orcid": "0000-0002-3237-2429"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Mei Ding",
      "orcid": "0000-0001-8146-1535"
    },
    {
      "affs": [
        6,
        1
      ],
      "name": "Anette Persson-kry"
    },
    {
      "affs": [
        6,
        1
      ],
      "name": "Sanhita Mitra"
    },
    {
      "affs": [
        6,
        1
      ],
      "name": "Tuğçe Munise Şatır",
      "orcid": "0000-0001-9021-1650"
    },
    {
      "affs": [
        6,
        1
      ],
      "name": "Bilada Bilican",
      "orcid": "0000-0002-3057-2654"
    },
    {
      "affs": [
        6,
        1
      ],
      "name": "Mirko Messa",
      "orcid": "0000-0001-7133-0152"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Graham Mathew Fraser",
      "orcid": "0000-0002-5733-201X"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "John E. Linley",
      "orcid": "0000-0001-6450-8805"
    },
    {
      "affs": [
        7,
        1
      ],
      "name": "Helen Plant"
    },
    {
      "affs": [
        7,
        1
      ],
      "name": "Rachel K. Moore",
      "orcid": "0000-0003-2388-071X"
    },
    {
      "affs": [
        8,
        1
      ],
      "name": "Tina Seifert"
    },
    {
      "affs": [
        9,
        1
      ],
      "name": "Michael Lerche"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Carina Raynochek"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Ewa Nilsson"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Nour K. Majbour",
      "orcid": "0000-0002-7544-8497"
    },
    {
      "affs": [
        10,
        1
      ],
      "name": "Richard Lucey"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Taianá Maia de Oliveira",
      "orcid": "0000-0003-3231-8112"
    },
    {
      "affs": [
        11,
        1
      ],
      "name": "Qi Wang",
      "orcid": "0000-0002-5077-6304"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Iain P. Chessell"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Perla Breccia",
      "orcid": "0000-0002-8552-9012"
    },
    {
      "affs": [
        12,
        1
      ],
      "name": "Rebecca E. Jarvis",
      "orcid": "0000-0001-7583-6548"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6gdq28f15hrdb.bib",
  "cited_by": 8,
  "doi": "10.1038/s42004-026-02074-8",
  "fulltext_url": null,
  "id": "6gdq28f15hrdb",
  "issns": [
    "2399-3669"
  ],
  "landing_url": "https://doi.org/10.1038/s42004-026-02074-8",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Nerve injury and regeneration"
    ]
  ],
  "openalex": "W4416302578",
  "pdf_url": "https://www.nature.com/articles/s42004-026-02074-8.pdf",
  "pmcid": "PMC13187307",
  "pmid": "42156967",
  "published": "2026-05-19",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/6gdq28f15hrdb.ris",
  "sources": [
    {
      "first_seen": "2026-11-11T13:20:32Z",
      "native_id": "W4416302578",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s42004-026-02074-8"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Nerve injury and regeneration",
      "subfield": "neuroscience"
    }
  ],
  "title": "The rise and fall of SARM1 base-exchange inhibitors",
  "title_text": "The rise and fall of SARM1 base-exchange inhibitors",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T13:21:08Z",
  "url": "https://research.draconitic.com/paper/6gdq28f15hrdb",
  "venue": "Communications Chemistry",
  "versions": []
}