Targeting oncogenic Src homology 2 domain-containing phosphatase 2 (SHP2) by inhibiting its protein-protein interactions
| Title: | Targeting oncogenic Src homology 2 domain-containing phosphatase 2 (SHP2) by inhibiting its protein-protein interactions |
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| Authors: | Bobone S.; Pannone L.; Biondi B.; Solman M.; Flex E.; Canale V. C.; Calligari P.; De Faveri C.; Gandini T.; Quercioli A.; Torini G.; Venditti M.; Lauri A.; Fasano G.; Hoeksma J.; Santucci V.; Cattani G.; Bocedi A.; Carpentieri G.; Tirelli V.; Sanchez M.; Peggion C.; Formaggio F.; Den Hertog J.; Martinelli S.; Bocchinfuso G.; Tartaglia M.; Stella L. |
| Contributors: | Bobone, S; Pannone, L; Biondi, B; Solman, M; Flex, E; Canale, Vc; Calligari, P; De Faveri, C; Gandini, T; Quercioli, A; Torini, G; Venditti, M; Lauri, A; Fasano, G; Hoeksma, J; Santucci, V; Cattani, G; Bocedi, A; Carpentieri, G; Tirelli, V; Sanchez, M; Peggion, C; Formaggio, F; Den Hertog, J; Martinelli, S; Bocchinfuso, G; Tartaglia, M; Stella, L |
| Publisher Information: | American Chemical Society |
| Publication Year: | 2021 |
| Collection: | Universitá degli Studi di Roma "Tor Vergata": ART - Archivio Istituzionale della Ricerca |
| Subject Terms: | Settore CHIM/02 - CHIMICA FISICA |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/34714648; info:eu-repo/semantics/altIdentifier/wos/WOS:000718382200030; volume:64; issue:21; firstpage:15973; lastpage:15990; numberofpages:18; journal:JOURNAL OF MEDICINAL CHEMISTRY; https://hdl.handle.net/2108/285307 |
| DOI: | 10.1021/acs.jmedchem.1c01371 |
| Availability: | https://hdl.handle.net/2108/285307; https://doi.org/10.1021/acs.jmedchem.1c01371 |
| Rights: | info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/3.0/it/ |
| Accession Number: | edsbas.2F7B70B6 |
| Database: | BASE |