Inhibiting EGFR Dimerization Using Triazolyl-Bridged Dimerization Arm Mimics

The epidermal growth factor receptor (EGFR) is overexpressed in multiple carcinomas and is the focus of a variety of targeted therapies. Here we report the design of peptide-based compounds that mimic the EGFR dimerization arm and inhibit allosteric activation of EGFR. These peptides are modified to contain a triazolyl bridge between the peptide strands to constrain the EGFR dimerization arm β-loop. In this study, we demonstrate that these peptides have significantly improved proteolytic stability over the non-modified peptide sequence, and their inhibitory effects are dependent on the number of the methylene units and orientation of the introduced triazolyl bridge. We identified a peptide, EDA2, which downregulates receptor phosphorylation and dimerization and reduces cell viability. This is the first example of a biologically active triazolyl-bridged peptide targeting the EGFR dimerization interface that effectively downregulates EGFR activation.表皮生长因子受体（epidermal growth factor receptor, EGFR）在多种癌症中呈过表达状态，亦是诸多靶向治疗的核心作用靶点。本研究报道了一类可模拟EGFR二聚化臂（dimerization arm）的肽类化合物，能够抑制EGFR的变构激活（allosteric activation）。此类肽经修饰，在两条肽链之间引入三唑基桥连（triazolyl bridge）结构，以约束EGFR二聚化臂的β环。本研究证实，相较于未修饰的原始肽序列，此类修饰肽的蛋白水解稳定性（proteolytic stability）显著提升，且其抑制效应取决于所引入三唑基桥连结构的亚甲基单元（methylene units）数目与空间取向。本研究筛选得到肽EDA2，该肽可下调受体磷酸化（receptor phosphorylation）与二聚化水平，并降低细胞活力（cell viability）。这是首个靶向EGFR二聚化界面（dimerization interface）、具备生物活性的三唑基桥连肽，可有效下调EGFR的激活。