Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Authors: Nina-Louisa Efrém, Machoud Amoussa, Yvette Roske, Feng Bo, Ziqiong Guo, Katrin Jana Frank, Szymon Pach, Clemens Alexander Wolf, Anton F. Ketzel, Varbina Ivanova, Silke Radetzki, Tibor Viktor Szalai, Claudia Fiñana, Guillaume Schmitz, Torben Falk, Leonardo Seidl, Jonas Janzen, Paul Curtis Schöpe, Victoria Zeitz, Jordi Juárez-Jiménez, Jens Peter von Kries, Ulrike Stein, Marina Lesina, Walter Birchmeier, Christoph Rademacher, Marco Cecchini, Laura Belver, Han Sun, György M. Keserű, Gerhard Wolber, Hana Algül, Jia Li, Oliver Daumke, Marc Nazaré
Institutions: Karlsruhe Institute of Technology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Freie Universität Berlin, Max Delbrück Center, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Technical University of Munich, Universitat de Barcelona, Budapest University of Technology and Economics, HUN-REN Research Centre for Natural Sciences, Josep Carreras Leukaemia Research Institute, Centre National de la Recherche Scientifique, Institut de Chimie de Strasbourg, Université de Strasbourg, University of Vienna, Bielefeld University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213985109