Studies on inhibitors for epidermal growth factor receptor based on oligopeptides which imitated pseudosubstrates

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1. Inhibition of autophosphorylation of epidermal growth factor receptor (EGFR) by oligopeptides having amino acid sequences around autophosphorylation sites of EGFR (Tyr992, Tyr1068, Tyr1148, Tyr1173) were studied. The peptides Ac-VPEYINQ-NH2, Ac-DYQQD-NH2, and Ac-ENAEYLR-NH2, which originate from Tyr1068, Tyr1148, and Tyr1173, respectively, were found to be effective in inhibiting autophosphorylation of EGFR. Effects of the replacement of tyrosine residue in each peptide by alanine, leucine, phenylalanine, or phosphotyrosine on inhibitory potencies of autophosphorylation were studied. Aromatic rings in the peptides were found to be essential for inhibitory potencies.2. Replacement of acidic amino acids in DYQQD and ENAEYLR by neutral amino acids greatly increased inhibitory potencies.3. Docking simulations showed that DYQQD and QNAQYLR are ATP-competitive inhibitors, whereas ENAEYLR and NYQQN are ATP-non-competitive inhibitors.4. Effects of ATP concentrations on inhibitory potencies were studied to see whether the oligopeptides are ATP-competitive inhibitors. Experimental results supported the results predicted by the docking simulations.5. It is expected that ATP-non-competitive inhibitors (ENAEYLR and NYQQN) are specific inhibitors for EGFR. Thus, especially, NYQQN is a promising seed for developing therapeutic agents for breast and lung cancers.