Fragment-based covalent targeting of lysines at the allosteric latch site of SHP2

Di Lorenzo, Vincenzo; Csorba, Noémi; Szabó, Renáta; Kollár, Levente; Roske, Yvette; Rand̵elović, Ivan; Balázs, Krisztina; Szalai, Tibor Viktor; Efrém, Nina-Louisa; Mihalovits, Levente; Imre, Tímea; Simon, József; Tóvári, József; Nazaré, Marc; Daumke, Oliver; Ábrányi-Balogh, Péter; Keserű, György M.

Fragment-based covalent targeting of lysines at the allosteric latch site of SHP2

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Item Type:	Article
Title:	Fragment-based covalent targeting of lysines at the allosteric latch site of SHP2
Creators:	Di Lorenzo, Vincenzo ORCID: https://orcid.org/0000-0002-3140-3561, Csorba, Noémi, Szabó, Renáta, Kollár, Levente ORCID: https://orcid.org/0000-0001-9679-3735, Roske, Yvette ORCID: https://orcid.org/0000-0001-6237-388X, Rand̵elović, Ivan, Balázs, Krisztina, Szalai, Tibor Viktor ORCID: https://orcid.org/0009-0000-4088-3117, Efrém, Nina-Louisa ORCID: https://orcid.org/0009-0000-6505-4120, Mihalovits, Levente, Imre, Tímea, Simon, József, Tóvári, József, Nazaré, Marc ORCID: https://orcid.org/0000-0002-1602-2330, Daumke, Oliver ORCID: https://orcid.org/0000-0002-6190-1414, Ábrányi-Balogh, Péter ORCID: https://orcid.org/0000-0002-9284-5160 and Keserű, György M. ORCID: https://orcid.org/0000-0003-1039-7809
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.
Keywords:	SHP2 Phosphatase, Covalent Inhibitor, Allosteric Modulator, Lysine Labelling, NHS-Ester, Dichlorotriazine, X-Ray Structure
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society
Volume:	69
Number:	19
Page Range:	21955-21971
Number of Pages:	17
Date:	8 October 2026
Official Publication:	https://doi.org/10.1021/acs.jmedchem.6c01030
PubMed:	View item in PubMed

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