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

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.