TY - JOUR
T1 - Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions
AU - Bobone, Sara
AU - Pannone, Luca
AU - Biondi, Barbara
AU - Solman, Maja
AU - Flex, Elisabetta
AU - Canale, Viviana Claudia
AU - Calligari, Paolo
AU - De Faveri, Chiara
AU - Gandini, Tommaso
AU - Quercioli, Andrea
AU - Torini, Giuseppe
AU - Venditti, Martina
AU - Lauri, Antonella
AU - Fasano, Giulia
AU - Hoeksma, Jelmer
AU - Santucci, Valerio
AU - Cattani, Giada
AU - Bocedi, Alessio
AU - Carpentieri, Giovanna
AU - Tirelli, Valentina
AU - Sanchez, Massimo
AU - Peggion, Cristina
AU - Formaggio, Fernando
AU - Den Hertog, Jeroen
AU - Martinelli, Simone
AU - Bocchinfuso, Gianfranco
AU - Tartaglia, Marco
AU - Stella, Lorenzo
N1 - Funding Information:
The authors gratefully acknowledge the Protein Array and Analysis Core at The University of Texas M. D. Anderson Cancer Center for performing the SH2 array experiments. This work was supported by the AIRC Foundation for Cancer Research in Italy (Grants IG19171 and IG24940 to L.S. and IG21614 to M.T.), the Italian Ministry of Education, University and Research (MIUR, Grant PRIN 20157WW5EH_007 to L.S.), Regione Lazio (Grant A0375-2020-36719 to L.S. and M.T.), the Italian Ministry of Health (Ricerca Corrente 2019 and 2020 to M.T.), the European Program on Rare Diseases (NSEuroNet, to M.T. and J.d.H.), the Partnership for Advanced Computing in Europe (PRACE, Grants 2019204928 and 2017174118 to G.B.), which awarded computational resources at CINECA (Italy) and CINECA (Grant HP10BL5G4C to G.B.). L.P. is a recipient of an AIRC research fellowship. S.B., P.C., G.B., and L.S. dedicate this article to Prof. Antonio Palleschi, on the occasion of his retirement.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/11/11
Y1 - 2021/11/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85118865928
U2 - 10.1021/acs.jmedchem.1c01371
DO - 10.1021/acs.jmedchem.1c01371
M3 - Article
C2 - 34714648
AN - SCOPUS:85118865928
SN - 0022-2623
VL - 64
SP - 15973
EP - 15990
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -