Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions

Sara Bobone, Luca Pannone, Barbara Biondi, Maja Solman, 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 TirelliMassimo Sanchez, Cristina Peggion, Fernando Formaggio, Jeroen den Hertog, Simone Martinelli, Gianfranco Bocchinfuso, Marco Tartaglia, Lorenzo Stella

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)15973-15990
Number of pages18
JournalJournal of medicinal chemistry
Volume64
Issue number21
DOIs
Publication statusPublished - 11 Nov 2021

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