Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions
| Autor: | Viviana Claudia Canale, Giuseppe Torini, Maja Solman, Cristina Peggion, Martina Venditti, Antonella Lauri, Giada Cattani, Gianfranco Bocchinfuso, Chiara De Faveri, Jelmer Hoeksma, Paolo Calligari, Sara Bobone, Giulia Fasano, Marco Tartaglia, Lorenzo Stella, Alessio Bocedi, Tommaso Gandini, Giovanna Carpentieri, Fernando Formaggio, Simone Martinelli, Jeroen den Hertog, Elisabetta Flex, Andrea Quercioli, Massimo Sanchez, Valentina Tirelli, Valerio Santucci, Barbara Biondi, Luca Pannone |
|---|---|
| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2021 |
| Předmět: |
SHP2 phosphatase
Allosteric regulation Phosphatase Mutant Peptide Protein Tyrosine Phosphatase Non-Receptor Type 11 Non-Receptor Type 11 Article Protein–protein interaction src Homology Domains Settore CHIM/02 Drug Discovery cancer Animals Binding Sites Mutation Protein Binding Signal Transduction Zebrafish Oncogenes chemistry.chemical_classification Src homology domain Chemistry rare diseases Cell biology Molecular Medicine Protein Tyrosine Phosphatase Signal transduction Function (biology) Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of Medicinal Chemistry Journal of medicinal chemistry, 64(21), 15973-15990. American Chemical Society Journal of medicinal chemistry (2021). doi:10.1021/acs.jmedchem.1c01371 info:cnr-pdr/source/autori:Bobone, Sara; Pannone, Luca; Biondi, Barbara; Solman, Maja; Flex, Elisabetta; Canale, Viviana Claudia; Calligari, Paolo; De Faveri, Chiara; Gandini, Tommaso; Quercioli, Andrea; Torini, Giuseppe; Venditti, Martina; Lauri, Antonella; Fasano, Giulia; Hoeksma, Jelmer; Santucci, Valerio; Cattani, Giada; Bocedi, Alessio; Carpentieri, Giovanna; Tirelli, Valentina; Sanchez, Massimo; Peggion, Cristina; Formaggio, Fernando; Den Hertog, Jeroen; Martinelli, Simone; Bocchinfuso, Gianfranco; Tartaglia, Marco; Stella, Lorenzo/titolo:Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions/doi:10.1021%2Facs.jmedchem.1c01371/rivista:Journal of medicinal chemistry/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in multiple signaling pathways and 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 on disease-associated SHP2 mutants. Based on the consideration that pathogenic lesions cause signaling hyperactivation due to increased SHP2 association with cognate proteins, we developed peptide-based molecules with low nM affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation and an affinity for pathogenic variants of SHP2 up to 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 to investigate the role of protein-protein interactions in the function of SHP2. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|