{
  "abstract": "Checkpoint kinase 2 (CHK2), a serine/threonine kinase encoded by CHEK2, plays a key role in the DNA damage response (DDR), acting downstream of ataxia-telangiectasia mutated (ATM) kinase in the ATM–CHK2–p53 signaling axis. Despite considerable interest in CHK2 as a potential therapeutic target, our understanding of its biological functions and therapeutic potential remains constrained by the limited availability of potent and selective chemical probes. While several non-covalent CHK2 inhibitors have been developed, their utility for interrogating CHK2 biology is often limited by suboptimal kinase selectivity. Moreover, selective covalent inhibitors that enable robust and sustained pharmacological perturbation of CHK2 have not been reported. To address this gap, we developed the covalent CHK2 inhibitor (R)-12b, which selectively targets Cys231 at the P3 position of the glycine-rich loop (P-loop). Covalent binding of (R)-12b induces a repositioning of the P-loop, leading to an outward displacement of the N-lobe and expansion of the ATP-binding pocket. (R)-12b exhibits nanomolar biochemical and cellular potency, good in vitro metabolic stability, moderate covalent bond-formation kinetics, and a highly favorable kinome-wide selectivity profile. Together, these properties establish (R)-12b as a first-in-class selective covalent CHK2 inhibitor and a valuable chemical tool for exploring CHK2 biology and further elucidating its therapeutic potential.",
  "abstract_shown": true,
  "affiliations": [
    "Department for Medicinal Chemistry, IBE, Faculty of Medicine, University of Tübingen, Auf der Morgenstelle 8, Tübingen, Germany, 72076",
    "Cluster of Excellence iFIT (EXC",
    "Functionally Instructed Tumor Therapies’, University of Tübingen",
    "Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences,Faculty of Sciences, University of Tübingen, Auf der Morgenstelle 8, Tübingen, Germany, 72076",
    "Department for Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, Auf der Morgenstelle 8, Tübingen, Germany, 72076",
    "Department for Pharmaceutical (Bio-)analysis, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, Auf der Morgenstelle 8, Tübingen, Germany, 72076",
    "Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Straße 15, Frankfurt am Main, Germany, 60438",
    "Institute of Pharmaceutical Chemistry, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Straße 9, Frankfurt am Main, Germany, 60438",
    "Frankfurt Cancer Institute (FCI) and German Translational Cancer Network (DKTK) Site Frankfurt/Mainz",
    "Tübingen Center for Academic Drug Discovery & Development (TüCAD2",
    "University of Tübingen",
    "Interfaculty Institute for Biomedical Informatics (IBMI, University of Tübingen, Sand 14, Tübingen, Germany, 72076"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Xiaojun Julia Liang"
    },
    {
      "affs": [
        4
      ],
      "name": "Janosch Rheinganz"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Fabian B. Kraft"
    },
    {
      "affs": [
        4
      ],
      "name": "Sven R. Aldea"
    },
    {
      "affs": [
        5
      ],
      "name": "Benedikt Masberg"
    },
    {
      "affs": [
        3
      ],
      "name": "Alexander Rasch"
    },
    {
      "affs": [
        6,
        7,
        8
      ],
      "name": "Martin P. Schwalm"
    },
    {
      "affs": [
        4
      ],
      "name": "Jason Stahlecker"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Janis Leske"
    },
    {
      "affs": [
        6,
        7,
        8
      ],
      "name": "Susanne Müller"
    },
    {
      "affs": [
        6,
        7,
        8
      ],
      "name": "Stefan Knapp"
    },
    {
      "affs": [
        1,
        2,
        3,
        9,
        10
      ],
      "name": "Stefan Laufer"
    },
    {
      "affs": [
        5
      ],
      "name": "Michael Lämmerhofer"
    },
    {
      "affs": [
        4,
        11
      ],
      "name": "Frank M. Böckler"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Matthias Gehringer",
      "orcid": "0000-0003-0163-3419"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7v2cc4kqdgq81.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009954/v1",
  "fulltext_url": null,
  "id": "7v2cc4kqdgq81",
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  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009954/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Synthesis and biological activity"
    ]
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  "openalex": "W7220730621",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009954/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-05",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/7v2cc4kqdgq81.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:22Z",
      "native_id": "10.26434/chemrxiv.15009954",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009954/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Synthesis and biological activity",
      "subfield": "organic"
    }
  ],
  "title": "Checkmate for CHK2: Discovery of First-in-Class Covalent CHK2 Inhibitors with High Potency and Selectivity",
  "title_text": "Checkmate for CHK2: Discovery of First-in-Class Covalent CHK2 Inhibitors with High Potency and Selectivity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:22Z",
  "url": "https://research.draconitic.com/paper/7v2cc4kqdgq81",
  "venue": "ChemRxiv",
  "versions": []
}