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 Tirelli; Massimo Sanchez; Cristina Peggion; Fernando Formaggio; Jeroen den Hertog; Simone Martinelli; Gianfranco Bocchinfuso; Marco Tartaglia; Lorenzo Stella

doi:10.1021/acs.jmedchem.1c01371

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

23 Citations (Scopus)

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 language	English
Pages (from-to)	15973-15990
Number of pages	18
Journal	Journal of medicinal chemistry
Volume	64
Issue number	21
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01371
Publication status	Published - 11 Nov 2021

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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., ... Stella, L. (2021). Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions. Journal of medicinal chemistry, 64(21), 15973-15990. https://doi.org/10.1021/acs.jmedchem.1c01371

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

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.",

author = "Sara Bobone and Luca Pannone and Barbara Biondi and Maja Solman and Elisabetta Flex and Canale, {Viviana Claudia} and Paolo Calligari and {De Faveri}, Chiara and Tommaso Gandini and Andrea Quercioli and Giuseppe Torini and Martina Venditti and Antonella Lauri and Giulia Fasano and Jelmer Hoeksma and Valerio Santucci and Giada Cattani and Alessio Bocedi and Giovanna Carpentieri and Valentina Tirelli and Massimo Sanchez and Cristina Peggion and Fernando Formaggio and {den Hertog}, Jeroen and Simone Martinelli and Gianfranco Bocchinfuso and Marco Tartaglia and Lorenzo Stella",

year = "2021",

month = nov,

day = "11",

doi = "10.1021/acs.jmedchem.1c01371",

language = "English",

volume = "64",

pages = "15973--15990",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "21",

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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 2021, 'Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions', Journal of medicinal chemistry, vol. 64, no. 21, pp. 15973-15990. https://doi.org/10.1021/acs.jmedchem.1c01371

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

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.

U2 - 10.1021/acs.jmedchem.1c01371

DO - 10.1021/acs.jmedchem.1c01371

M3 - Article

C2 - 34714648

SN - 0022-2623

VL - 64

SP - 15973

EP - 15990

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 21

ER -

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

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