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

Abstract

Mutations of PTPN11, the gene coding for the Src homology 2 domain-containing phosphatase 2 (SHP2), cause childhood leukemias and developmental disorders. SHP2 inhibitors targeting the catalytic site or an allosteric pocket lack specificity or are ineffective on pathogenic variants. In addition, several data indicate that increased association with cognate proteins, through its SH2 domains, rather than enhanced catalytic activity, is the main effect of mutations causing hyperactivation of SHP2-mediated signaling. We developed peptide-based molecules with low nM affinity to the N-SH2 domain and high specificity. These molecules bind to pathogenic variants of SHP2 with an affinity up to 20 times higher than to the wild-type protein, in contrast to allosteric inhibitors, and were able to revert the effects of a pathogenic SHP2 mutation 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.TABLE OF CONTENTS GRAPHICS

Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy

“…CF-P9W5 displayed 2−20 times higher affinity to pathogenic variants over wild-type SHP2 and rescued the mortality and developmental defects induced by pathogenic mutations, offering an alternative way for treating SHP2 mutants-associated diseases. 26 While serving as the downstream signal of programed death 1 (PD-1), SHP2 also played crucial roles in PD-1/PD-L1 pathway through impairing the immunosuppressive effect of PD-1. 63 Methylene blue (MB), an FDA-approved drug for treating methemoglobinemia, interpreted the interaction between N-SH2 of SHP2 and PD-1, thus potently inhibiting the PD-1 signaling axis 25 (Figure 7).…”

Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings

“…42 The variable clinical features of NF1 patients associated with PTPN11 variants documented in the present work and previous reports and the emerging drugs able to block SHP2 function suggest a possible alternative therapeutic strategy to treat evolutive complications of this disorder by inhibiting SHP2 function. 43,44 However, it should be noted that neurofibromin is a large multi-domain protein, whose regulatory function is likely linked to other signaling pathways and cellular processes, including actin cytoskeleton remodeling, cell adhesion, and intracellular trafficking. 45…”

New prospectives on treatment opportunities in RASopathies

“…These inhibitors, including RMC‐4630, TNO155, and RLY‐1971, are unable to bind to SHP‐2 mutants in which the auto‐inhibited conformation is destabilized (Padua et al, 2018); therefore, these inhibitors are unlikely to be active for most PTPN11 alleles in NS, which do perturb SHP‐2 auto‐inhibition. This limitation may be prevented in a novel approach that targets the N‐terminal Src homology domain of SHP2, allowing mutant SHP2 to be targeted (Bobone et al, 2021). Through their inhibitory role on the nexus of RAS exchange, RMC‐4630 and related SHP‐2 inhibitors may be effective in RASopathies caused by variants in genes other than PTPN11 , although this hypothesis has not yet been tested.…”