Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2
Abstract Covalent mechanism of action is a powerful way to modulate challenging drug targets. Here, we present a streamlined workflow that combines covalent fragment screening (electrophile first approach) and ligand-first strategy to identify covalent inhibitors targeting lysine residues in the allosteric latch site of SHP2 phosphatase. Supported by complementary computational and experimental analyses, this strategy enabled us to identify the first potent cell active allosteric covalent inhibitors acting at this site. Demonstrating the covalent tractability of the latch site opens further avenues for future optimization and therapeutic exploration of high-value allosteric SHP2 inhibitors.
Authors
- Péter Ábrányi‐Balogh (ORCID: https://orcid.org/0000-0002-9284-5160)
- Levente Kollár (ORCID: https://orcid.org/0000-0001-9679-3735)
- György M. Keserű (ORCID: https://orcid.org/0000-0003-1039-7809)
- Tı́mea Imre (ORCID: https://orcid.org/0000-0001-5830-8137)
- Renáta Szabó
- Noémi Csorba (ORCID: https://orcid.org/0009-0007-5711-450X)
- V. di Lorenzo (ORCID: https://orcid.org/0000-0002-3140-3561)
- Marc Nazaré (ORCID: https://orcid.org/0000-0002-1602-2330)
- Levente Mihalovits
- Nina‐Louisa Efrém (ORCID: https://orcid.org/0009-0000-6505-4120)
- József Tóvári (ORCID: https://orcid.org/0000-0002-5543-3204)
- Ivan Ranđelović (ORCID: https://orcid.org/0000-0003-0161-0022)
- József Simon
- Tibor Viktor Szalai
- Yvette Roske
- Oliver Daumke
- Krisztina Balázs
Institutions
- Karlsruhe Institute of Technology (DE)
- Bielefeld University (DE)
- Hochschule Bielefeld (DE)
- Max Delbrück Center (DE)
- Budapest University of Technology and Economics (HU)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- National Institute of Oncology (HU)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-09-18
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01030
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Magyar Tudományos Akadémia
- Nemzeti Kutatási Fejlesztési és Innovációs Hivatal