Allosteric Inhibition of the Epidermal Growth Factor Receptor

We previously reported a family of hydrocarbon-stapled peptides designed to interact with the epidermal growth factor receptor (EGFR) juxtamembrane (JM) segment, blocking its ability to form a coiled coil dimer that is essential for receptor activation. These hydrocarbon-stapled peptides, most notably E1(S), decreased the proliferation of cell lines that express wild-type EGFR (H2030 and A431) as well as those expressing the oncogenic mutants EGFR L858R (H3255) and L858R/T790M (H1975). Although our previous investigations provided evidence that E1(S) interacted with EGFR directly, the location and details of these interactions were not established. Here we apply biochemical and cross-linking mass spectrometry tools to better define the interactions between E1(S) and EGFR. Taken with previously reported structure-activity relationships, our results support a model in which E1(S) interacts simultaneously with both the JM and the C-lobe of the activator kinase, effectively displacing the JM of the receiver kinase. Our results also reveal potential interactions between E1(S) and the N-terminal region of the C-terminal tail. We propose a model in which E1(S) inhibits EGFR by both mimicking and inhibiting JM coiled coil formation. This model could be used to design novel, allosteric (and perhaps nonpeptidic) EGFR inhibitors.

Automated summary

In this study, a family of hydrocarbon-stapled peptides, including E1(S), was found to interact with EGFR and inhibit its activity by disrupting JM coiled coil formation. These findings suggest a potential strategy for designing novel allosteric EGFR inhibitors based on mimicking and inhibiting JM interactions.