Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2

Di Lorenzo, Vincenzo and Csorba, Noémi and Szabó, Renáta and Kollár, Levente and Roske, Yvette and Rand̵elović, Ivan and Balázs, Krisztina and Szalai, Tibor Viktor and Efrém, Nina-Louisa and Mihalovits, Levente and Imre, Timea and Simon, József and Tóvári, József and Nazaré, Marc and Daumke, Oliver and Ábrányi-Balogh, Péter and Keserű, György Miklós (2026) Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2. JOURNAL OF MEDICINAL CHEMISTRY. ISSN 0022-2623 (print); 1520-4804 (online)

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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.

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