{
  "abstract": "The cytosolic protein tyrosine phosphatase SHP2 is an emerging therapeutic target due to its central role in oncogenic receptor tyrosine kinase and immune checkpoint signaling. Although allosteric SHP2 inhibitors have entered clinical trials, they often lack efficacy as single agents and display reduced potency against activated SHP2 mutants. New allosteric SHP2 inhibitor chemotypes and a deeper understanding of allosteric SHP2 modulation are therefore needed. Herein, we report N -aryl-1 H -azaindazoles as a novel class of allosteric SHP2 inhibitors. A scaffold-hopping strategy led to the conversion of an orthosteric SHP2 inhibitor into an allosteric inhibitor. Structure-activity relationship studies, including a systematic investigation of the scaffold, led to the identification of compound 67 . Compound 67 inhibits SHP2 through an exclusively allosteric mechanism and shows potent activity across various cancer cell lines, including AML cells overexpressing the activated SHP2 E76K mutant. X-ray crystallography and computational analyses elucidated key molecular determinants underlying the steep structureactivity relationships of this inhibitor series, providing a structural basis for further optimization.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP, Campus Berlin-Buch, Robert-Rössle-Str. 10, Berlin, Germany, 13125",
    "Institute of Organic Chemistry, Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, Karlsruhe, Germany, 76131",
    "Institute of Pharmacy, Molecular Design Group, Freie Universität, Königin-Luise-Str. 2–4, Berlin, Germany, 14195",
    "Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin, Germany, 13125",
    "Shanghai Institute of Materia Medica (SIMM, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai, China",
    "School of Medicine and Health",
    "Technical University of Munich",
    "School of Pharmacy and Food Science, University of Barcelona, Av Joan XXIII 27-31, Barcelona, Spain, 08028",
    "Research Centre for Natural Sciences (RCNS, Medicinal Chemistry, Magyar Tudósok Körútja 2, Budapest, Hungary, 1117",
    "Department of Inorganic and Analytical Chemistry, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3., Budapest, Hungary, H-1111",
    "Josep Carreras Leukemia Research Institute (IJC, Carretera de Can Ruti, Camí de les Escoles, s/n, Badalona, Barcelona, Spain, 08916",
    "Institut de Chimie de Strasbourg, CNRS, Université de Strasbourg",
    "Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria, 1090",
    "Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria, 1090",
    "Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, Bielefeld, Germany, 33615"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 34,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Nina-Louisa Efrém"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Machoud Amoussa"
    },
    {
      "affs": [
        3
      ],
      "name": "Yvette Roske"
    },
    {
      "affs": [
        4
      ],
      "name": "Feng Bo"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Ziqiong Guo"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Katrin Jana Frank"
    },
    {
      "affs": [
        2
      ],
      "name": "Szymon Pach"
    },
    {
      "affs": [
        2
      ],
      "name": "Clemens Alexander Wolf"
    },
    {
      "affs": [
        0
      ],
      "name": "Anton F. Ketzel"
    },
    {
      "affs": [
        7
      ],
      "name": "Varbina Ivanova"
    },
    {
      "affs": [
        0
      ],
      "name": "Silke Radetzki"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Tibor Viktor Szalai"
    },
    {
      "affs": [
        10
      ],
      "name": "Claudia Fiñana"
    },
    {
      "affs": [
        11
      ],
      "name": "Guillaume Schmitz"
    },
    {
      "affs": [
        12,
        13
      ],
      "name": "Torben Falk"
    },
    {
      "affs": [
        0
      ],
      "name": "Leonardo Seidl"
    },
    {
      "affs": [
        0
      ],
      "name": "Jonas Janzen"
    },
    {
      "affs": [
        3
      ],
      "name": "Paul Curtis Schöpe"
    },
    {
      "affs": [
        0
      ],
      "name": "Victoria Zeitz"
    },
    {
      "affs": [
        7
      ],
      "name": "Jordi Juárez-Jiménez"
    },
    {
      "affs": [
        0
      ],
      "name": "Jens Peter von Kries"
    },
    {
      "affs": [
        3
      ],
      "name": "Ulrike Stein"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Marina Lesina"
    },
    {
      "affs": [
        3
      ],
      "name": "Walter Birchmeier"
    },
    {
      "affs": [
        12
      ],
      "name": "Christoph Rademacher"
    },
    {
      "affs": [
        11
      ],
      "name": "Marco Cecchini"
    },
    {
      "affs": [
        10
      ],
      "name": "Laura Belver"
    },
    {
      "affs": [
        0
      ],
      "name": "Han Sun"
    },
    {
      "affs": [
        8
      ],
      "name": "György M. Keserű"
    },
    {
      "affs": [
        2
      ],
      "name": "Gerhard Wolber"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Hana Algül"
    },
    {
      "affs": [
        4
      ],
      "name": "Jia Li"
    },
    {
      "affs": [
        3
      ],
      "name": "Oliver Daumke"
    },
    {
      "affs": [
        0,
        14
      ],
      "name": "Marc Nazaré",
      "orcid": "0000-0002-1602-2330"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dmwm4r2pzaes7.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009247/v1",
  "fulltext_url": null,
  "id": "dmwm4r2pzaes7",
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  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009247/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",
      "1312|Protein Tyrosine Phosphatases"
    ]
  ],
  "openalex": "W7213985109",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009247/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-22",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/dmwm4r2pzaes7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:21Z",
      "native_id": "10.26434/chemrxiv.15009247",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009247/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Tyrosine Phosphatases",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric",
  "title_text": "Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:21Z",
  "url": "https://research.draconitic.com/paper/dmwm4r2pzaes7",
  "venue": "ChemRxiv",
  "versions": []
}