{
  "abstract": "Mutations of EIF2AK4, which encodes the eIF2α kinase GCN2, cause a severe inherited form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD). Some pathogenic variants of GCN2 are amenable to pharmacological reactivation by low concentrations of ATP pocket-binding inhibitors. Kinase inhibition at modestly elevated concentrations limits the clinical utility of these drugs against PVOD. We therefore performed an in cellulo chemical screen for GCN2 activators and identified three structurally distinct compounds with low micromolar stimulatory activities. Unlike previously described GCN2 activators, one of these molecules activated GCN2 independently of GCN1. Modelling supported by structure activity screens suggested it binds within the ATP pocket of GCN2, but unlike existing ligands does not protrude inward into the allosteric pocket or outward into the solvent. This overcomes a key requirement of other GCN2 activators.",
  "abstract_shown": true,
  "affiliations": [
    "Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, United Kingdom",
    "Division of Cancer Research, School of Medicine, Ninewells Hospital, Dundee, United Kingdom",
    "The ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, United Kingdom",
    "Department of Medicine, University of Cambridge, Cambridge, United Kingdom",
    "Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom",
    "Domainex Ltd, Churchill Building, Chesterford Research Park, Saffron Walden, United Kingdom",
    "Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom",
    "Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom",
    "Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "JiaYi Zhu",
      "orcid": "0000-0001-7401-6468"
    },
    {
      "affs": [
        0
      ],
      "name": "Giulia Emanuelli",
      "orcid": "0000-0001-8899-6110"
    },
    {
      "affs": [
        1
      ],
      "name": "Glenn Robert Masson",
      "orcid": "0000-0002-1386-4719"
    },
    {
      "affs": [
        1
      ],
      "name": "Vanessa Vinciauskaite"
    },
    {
      "affs": [
        2
      ],
      "name": "Henriette Willems",
      "orcid": "0000-0001-7196-5975"
    },
    {
      "affs": [
        0
      ],
      "name": "Peiqiao Cai"
    },
    {
      "affs": [
        2
      ],
      "name": "Andrew Lim"
    },
    {
      "affs": [
        2
      ],
      "name": "Christopher Alan Brown"
    },
    {
      "affs": [
        2
      ],
      "name": "David Winpenny"
    },
    {
      "affs": [
        3
      ],
      "name": "Murray Clarke"
    },
    {
      "affs": [
        4
      ],
      "name": "Rebecca Gilley"
    },
    {
      "affs": [
        5
      ],
      "name": "Fergus Preston"
    },
    {
      "affs": [
        6
      ],
      "name": "Jordan CJ Wilson"
    },
    {
      "affs": [
        6
      ],
      "name": "Aldo Bader"
    },
    {
      "affs": [
        7
      ],
      "name": "Taufiq Rahman"
    },
    {
      "affs": [
        0
      ],
      "name": "Joseph E Chambers",
      "orcid": "0000-0003-4675-0053"
    },
    {
      "affs": [
        2
      ],
      "name": "John Skidmore"
    },
    {
      "affs": [
        3,
        8
      ],
      "name": "Nicholas W Morrell"
    },
    {
      "affs": [
        0,
        3,
        8
      ],
      "name": "Stefan J Marciniak",
      "orcid": "0000-0001-8472-7183"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4qer857jsnrrn.bib",
  "cited_by": 1,
  "doi": "10.7554/elife.108590",
  "fulltext_url": "https://elifesciences.org/articles/108590",
  "id": "4qer857jsnrrn",
  "issns": [
    "2050-084X"
  ],
  "landing_url": "https://elifesciences.org/articles/108590",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "elife",
      "cell-biology"
    ],
    [
      "heading",
      "Cell Biology"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2740|Pulmonary Hypertension Research and Treatments"
    ]
  ],
  "openalex": "W4414534296",
  "pdf_url": "https://cdn.elifesciences.org/articles/108590/elife-108590-v1.pdf",
  "pmcid": "PMC13713030",
  "pmid": "42945303",
  "published": "2026-10-27",
  "publisher": "eLife Sciences Publications",
  "ris": "https://research.draconitic.com/paper/4qer857jsnrrn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:25Z",
      "native_id": "108590",
      "source": "elife",
      "url": "https://elifesciences.org/articles/108590"
    },
    {
      "first_seen": "2026-10-31T12:23:30Z",
      "native_id": "PMC13713030",
      "source": "pmc",
      "url": "https://doi.org/10.7554/elife.108590"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "elife:cell-biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "A GCN1-independent activator of the kinase GCN2",
  "title_text": "A GCN1-independent activator of the kinase GCN2",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:30Z",
  "url": "https://research.draconitic.com/paper/4qer857jsnrrn",
  "venue": "eLife",
  "versions": []
}