{
  "abstract": "Isocitrate dehydrogenase 1 (IDH1) catalyses the interconversion of isocitrate and -ketoglutarate and is overexpressed in several cancers, supporting tumour survival and treatment resistance. Inhibitors targeting the oncogenic mutant forms of IDH1 also inhibit the wild-type (WT) protein, but lose substantial potency due to greater competition with native substrates (isocitrate and Mg2+). We hypothesised that a covalent inhibitor may be more effective at overcoming the higher substrate affinity of wild-type IDH1. Here, a covalent fragment-based approach was used to develop IDH1-C269 selective inhibitors which prevent the key regulatory segment from forming an -helix required for catalytic competency. Following the identification of C269-selective fragments, we used X-ray crystallography to characterise IDH1-fragment bound complexes and guide structure-based design efforts. Inspired by the unexpected detection of bound isocitrate molecule in an X-ray crystal structure, fragment expansion yielded a series of compounds exploiting both an adjacent site and a unique water-mediated hydrogen bonding network. This series achieved strong potency (reaching IC50 = 47.5 nM, a 155-fold improvement in potency relative to the original fragment), retained activity in the presence of competing Mg2+, showed selectivity against IDH2 and reduced NADPH concentrations in a relevant PDAC cell model. Together, these findings present a mechanistic rationale for the covalent targeting of wild-type IDH1 and provide structurally validated inhibitors for further development.",
  "abstract_shown": true,
  "affiliations": [
    "Imperial College London"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "C. P. Brown"
    },
    {
      "name": "E. O. Harmer"
    },
    {
      "name": "A. Azam"
    },
    {
      "name": "C. Sharp"
    },
    {
      "name": "S. Horrell"
    },
    {
      "name": "J. A. Bull"
    },
    {
      "name": "A. Armstrong"
    },
    {
      "affs": [
        0
      ],
      "name": "D. Mann"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3ff7mseefga6b.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.24.753951",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753951v1.full",
  "id": "3ff7mseefga6b",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753951v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "1605|Synthesis and biological activity"
    ]
  ],
  "openalex": "W7214355731",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753951v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3ff7mseefga6b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:31Z",
      "native_id": "10.64898/2026.09.24.753951",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753951v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Discovery of Covalent Wild-Type Isocitrate Dehydrogenase 1 (IDH1) Inhibitors Targeting Cys269",
  "title_text": "Discovery of Covalent Wild-Type Isocitrate Dehydrogenase 1 (IDH1) Inhibitors Targeting Cys269",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:31Z",
  "url": "https://research.draconitic.com/paper/3ff7mseefga6b",
  "venue": "bioRxiv",
  "versions": []
}