{
  "abstract": "MAPK-activated protein kinase 2 (MAPKAPK2, MK2) is a downstream substrate of p38 MAPK that regulates inflammatory signaling and cytokine synthesis, making it an attractive therapeutic target. Although several crystal structures of MAPKAPK2 with ATP-competitive inhibitors have supported drug discovery, structural elucidation of selective non-ATP-competitive inhibitors has remained challenging. MK-25 is a non-ATP-competitive furan-2-carboxamide MAPKAPK2 inhibitor developed at Merck to overcome the selectivity and cellular-efficacy limitations of ATP-competitive chemotypes. Here, we show through isothermal titration calorimetry that MK-25 binds the activated MAPKAPK2, consistent with state-dependent allosteric binding. To determine the binding mode of MK-25, we solved a 2.8 A resolution crystal structure of an activated MAPKAPK2 construct in ternary complex with the ATP-site inhibitor PF-3644022 and a bromo-analogue of MK-25. The ligand occupies a pocket in the C-lobe overlapping the protein-substrate recognition region and formed through rearrangements of D and G helices and the activation segment. These interactions are consistent with the structure-activity relationships reported for the furan-2-carboxamide chemotype and identify a ligandable allosteric pocket that may facilitate future structure-guided design of selective, non-ATP-competitive MAPKAPK2 inhibitors.",
  "abstract_shown": true,
  "affiliations": [
    "Evotec"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "E. J. Beaumont"
    },
    {
      "name": "S. Duclos"
    },
    {
      "name": "S. Thieffine"
    },
    {
      "name": "r. Yadav"
    },
    {
      "name": "j. Barker"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2j749364epc60.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.01.755332",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755332v1.full",
  "id": "2j749364epc60",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755332v1",
  "language": null,
  "licence": "CC-BY-ND",
  "licence_label": "CC BY-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "1312|Protein Kinase Regulation and GTPase Signaling"
    ]
  ],
  "openalex": "W7220856198",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755332v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2j749364epc60.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:28Z",
      "native_id": "10.64898/2026.10.01.755332",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755332v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Crystal structure of activated MAPKAPK2 kinase reveals a C-lobe allosteric pocket for furan-2-carboxamide inhibitors",
  "title_text": "Crystal structure of activated MAPKAPK2 kinase reveals a C-lobe allosteric pocket for furan-2-carboxamide inhibitors",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:28Z",
  "url": "https://research.draconitic.com/paper/2j749364epc60",
  "venue": "bioRxiv",
  "versions": []
}