{
  "abstract": "Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile–drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile–drug conjugates is analogous to that of antibody–drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, The University of Texas at Austin, Austin, TX USA",
    "Department of Biochemistry, University of Washington, Seattle, WA USA",
    "Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX USA",
    "Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV USA",
    "Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xiaoding Jiang",
      "orcid": "0000-0002-4288-476X"
    },
    {
      "affs": [
        1
      ],
      "name": "Eric M. Lynch",
      "orcid": "0000-0001-5897-5167"
    },
    {
      "affs": [
        2
      ],
      "name": "Congcong Lyu"
    },
    {
      "affs": [
        2
      ],
      "name": "Crystal N. Wilson"
    },
    {
      "affs": [
        1
      ],
      "name": "Lauren E. Salay"
    },
    {
      "affs": [
        3
      ],
      "name": "Hayden T. Hess"
    },
    {
      "affs": [
        2
      ],
      "name": "Scott N. Lyons"
    },
    {
      "affs": [
        2
      ],
      "name": "Mu-Jie Lu",
      "orcid": "0000-0002-2174-1153"
    },
    {
      "affs": [
        0
      ],
      "name": "Shuangyu Luo"
    },
    {
      "affs": [
        0
      ],
      "name": "Gibae Kim"
    },
    {
      "affs": [
        2
      ],
      "name": "Hsin-Ru Chan"
    },
    {
      "affs": [
        0
      ],
      "name": "Wesley J. Wolfe"
    },
    {
      "affs": [
        4
      ],
      "name": "Lauren G. Zacharias"
    },
    {
      "affs": [
        4
      ],
      "name": "Thomas P. Mathews",
      "orcid": "0000-0002-9355-8243"
    },
    {
      "affs": [
        0
      ],
      "name": "Yi-Chih Lin",
      "orcid": "0000-0002-6498-215X"
    },
    {
      "affs": [
        3
      ],
      "name": "Bradley A. Webb",
      "orcid": "0000-0002-5299-2852"
    },
    {
      "affs": [
        1
      ],
      "name": "Justin M. Kollman"
    },
    {
      "affs": [
        2
      ],
      "name": "Xiaolu A. Cambronne",
      "orcid": "0000-0002-3547-448X"
    },
    {
      "affs": [
        0
      ],
      "name": "Ku-Lung Hsu",
      "orcid": "0000-0001-5620-3972"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/btjn0ytc4eefr.bib",
  "cited_by": 1,
  "doi": "10.1038/s41589-026-02289-9",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710160/",
  "id": "btjn0ytc4eefr",
  "issns": [
    "1552-4450",
    "1552-4469"
  ],
  "landing_url": "https://doi.org/10.1038/s41589-026-02289-9",
  "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",
      "1306|Cancer, Hypoxia, and Metabolism"
    ]
  ],
  "openalex": "W4414808041",
  "pdf_url": "https://www.nature.com/articles/s41589-026-02289-9.pdf",
  "pmcid": "PMC13710160",
  "pmid": "42557312",
  "published": "2026-08-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/btjn0ytc4eefr.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:11Z",
      "native_id": "PMC13710160",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41589-026-02289-9"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer, Hypoxia, and Metabolism",
      "subfield": "oncology"
    }
  ],
  "title": "A covalent PFKL activator suppresses tumor growth",
  "title_text": "A covalent PFKL activator suppresses tumor growth",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:11Z",
  "url": "https://research.draconitic.com/paper/btjn0ytc4eefr",
  "venue": "Nature Chemical Biology",
  "versions": []
}