PreprintCC BYChemRxiv
Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric
15 affiliations
- 1Department of Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP, Campus Berlin-Buch, Robert-Rössle-Str. 10, Berlin, Germany, 13125
- 2Institute of Organic Chemistry, Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, Karlsruhe, Germany, 76131
- 3Institute of Pharmacy, Molecular Design Group, Freie Universität, Königin-Luise-Str. 2–4, Berlin, Germany, 14195
- 4Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin, Germany, 13125
- 5Shanghai Institute of Materia Medica (SIMM, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai, China
- 6School of Medicine and Health
- 7Technical University of Munich
- 8School of Pharmacy and Food Science, University of Barcelona, Av Joan XXIII 27-31, Barcelona, Spain, 08028
- 9Research Centre for Natural Sciences (RCNS, Medicinal Chemistry, Magyar Tudósok Körútja 2, Budapest, Hungary, 1117
- 10Department of Inorganic and Analytical Chemistry, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3., Budapest, Hungary, H-1111
- 11Josep Carreras Leukemia Research Institute (IJC, Carretera de Can Ruti, Camí de les Escoles, s/n, Badalona, Barcelona, Spain, 08916
- 12Institut de Chimie de Strasbourg, CNRS, Université de Strasbourg
- 13Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria, 1090
- 14Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria, 1090
- 15Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, Bielefeld, Germany, 33615
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.
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BibTeX
@misc{efrem2026switching,
title = {{Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric}},
author = {Nina-Louisa Efrém and Machoud Amoussa and Yvette Roske and Feng Bo and Ziqiong Guo and Katrin Jana Frank and Szymon Pach and Clemens Alexander Wolf and Anton F. Ketzel and Varbina Ivanova and Silke Radetzki and Tibor Viktor Szalai and Claudia Fiñana and Guillaume Schmitz and Torben Falk and Leonardo Seidl and Jonas Janzen and Paul Curtis Schöpe and Victoria Zeitz and Jordi Juárez-Jiménez and Jens Peter von Kries and Ulrike Stein and Marina Lesina and Walter Birchmeier and Christoph Rademacher and Marco Cecchini and Laura Belver and Han Sun and György M. Keserű and Gerhard Wolber and Hana Algül and Jia Li and Oliver Daumke and Marc Nazaré},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009247/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009247/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric
AU - Nina-Louisa Efrém
AU - Machoud Amoussa
AU - Yvette Roske
AU - Feng Bo
AU - Ziqiong Guo
AU - Katrin Jana Frank
AU - Szymon Pach
AU - Clemens Alexander Wolf
AU - Anton F. Ketzel
AU - Varbina Ivanova
AU - Silke Radetzki
AU - Tibor Viktor Szalai
AU - Claudia Fiñana
AU - Guillaume Schmitz
AU - Torben Falk
AU - Leonardo Seidl
AU - Jonas Janzen
AU - Paul Curtis Schöpe
AU - Victoria Zeitz
AU - Jordi Juárez-Jiménez
AU - Jens Peter von Kries
AU - Ulrike Stein
AU - Marina Lesina
AU - Walter Birchmeier
AU - Christoph Rademacher
AU - Marco Cecchini
AU - Laura Belver
AU - Han Sun
AU - György M. Keserű
AU - Gerhard Wolber
AU - Hana Algül
AU - Jia Li
AU - Oliver Daumke
AU - Marc Nazaré
PY - 2026
DA - 2026/09/22
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009247/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009247/v1
AB - 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.
ER -