{
  "abstract": "Fatty acid synthase (FASN) is the sole enzyme capable of lipogenesis in cells and is upregulated in many cancers. Herein we report the discovery and development of SBP-5917 (78S), a novel, reversible, small-molecule probe which targets the thioesterase (TE) domain of FASN. SBP-5917 and other compounds in the series possess IC50 < 1 M and < 5 M for inhibiting recombinantly purified FASN-TE and cellular FASN respectively. Co-crystal structures of our inhibitors bound to the FASN-TE domain show that they are positioned in the substrate tunnel of the enzyme. Biochemical and biophysical analyses quantify the strength of compound binding and demonstrate their selectivity for FASN-TE. Preliminary pharmacokinetic studies indicate promising in vivo potency for many of the compounds in the series. SBP-5917 is the first structurally validated, reversible inhibitor of FASN-TE with demonstrated cellular target engagement and can serve as a chemical probe to investigate FASN as a therapeutic target.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Therapeutics Discovery, Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Instit"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "name": "J. Fromm"
    },
    {
      "name": "A. Aleshin"
    },
    {
      "name": "L. J. Lambert"
    },
    {
      "name": "L. De Backer"
    },
    {
      "name": "S. Reddy Ganji"
    },
    {
      "name": "M. E. Mattmann"
    },
    {
      "name": "A. S. Limpert"
    },
    {
      "name": "P. Gosalia"
    },
    {
      "name": "C. D. Wimer"
    },
    {
      "name": "F. I. A. L. Layng"
    },
    {
      "name": "M. Celeridad"
    },
    {
      "name": "R. Ardecky"
    },
    {
      "name": "P. Teriete"
    },
    {
      "name": "D. A. Scott"
    },
    {
      "name": "M. P. Hedrick"
    },
    {
      "name": "J. W. Smith"
    },
    {
      "name": "D. J. Sheffler"
    },
    {
      "affs": [
        0
      ],
      "name": "N. D. P. Cosford"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2qk271bnm81d0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.01.756096",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756096v1.full",
  "id": "2qk271bnm81d0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756096v1",
  "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",
      "cell biology"
    ],
    [
      "openalex",
      "1306|Cancer, Lipids, and Metabolism"
    ]
  ],
  "openalex": "W7220849957",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756096v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2qk271bnm81d0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:24Z",
      "native_id": "10.64898/2026.10.01.756096",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756096v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase",
  "title_text": "Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:24Z",
  "url": "https://research.draconitic.com/paper/2qk271bnm81d0",
  "venue": "bioRxiv",
  "versions": []
}