Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein–Protein Interactions
Sara Bobone, Luca Pannone, Barbara Biondi, Maja Šolman, Elisabetta Flex, Viviana Claudia Canale, Paolo Calligari, Chiara De Faveri, Tommaso Gandini, Andrea Quercioli, Giuseppe Torini, Martina Venditti, Antonella Lauri, Giulia Fasano, Jelmer Hoeksma, Valerio Santucci, Giada Cattani, Alessio Bocedi, Giovanna Carpentieri, Valentina Tirelli, Massimo Sanchez, Cristina Peggion, Fernando Formaggio, Jeroen den Hertog, Simone Martinelli, Gianfranco Bocchinfuso, Marco Tartaglia, Lorenzo Stella
Abstract
We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein-protein interactions in the function of SHP2.