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

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

 J. Med. Chem. 2026; https://doi.org/10.1021/acs.jmedchem.6c01030

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.