PUBLICATION
Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions
- 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.
- ID
- ZDB-PUB-211030-13
- Date
- 2021
- Source
- Journal of medicinal chemistry 64(21): 15973-15990 (Journal)
- Registered Authors
- den Hertog, Jeroen
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- Mutation
- Oncogenes*
- Protein Binding
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors*
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
- Signal Transduction
- Zebrafish/embryology
- src Homology Domains/drug effects*
- PubMed
- 34714648 Full text @ J. Med. Chem.
Citation
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. (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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping