Discovery of Cyclic Peptidomimetic Ligands Targeting the Extracellular Domain of EGFR

It
is very promising to target the extracellular domain of epidermal
growth factor receptor (EGFR) for developing novel and selective anticancer
therapies. Herein, we report the discovery of a novel small molecule, M-2-5, from a one-bead-two-compound (OBTC) cyclic γ-AApeptide
library. The molecule was found to bind tightly to the extracellular
domain of EGFR. Intriguingly, this molecule could also effectively
antagonize EGF-stimulated EGFR phosphorylation and downstream signal
transduction. Furthermore, together with its remarkable resistance
to proteolytic degradation, M-2-5 was shown to effectively
inhibit cell proliferation and migration in vitro and suppresses the
growth of tumor in the A549 xenograft model in vivo, highlighting
its potential therapeutic application for cancer treatment.