RRC ID 56593
著者 Toyama K, Kobayakawa T, Nomura W, Tamamura H.
タイトル Inhibition of EGFR Activation by Bivalent Ligands Based on a Cyclic Peptide Mimicking the Dimerization Arm Structure of EGFR.
ジャーナル Chem Pharm Bull (Tokyo)
Abstract The epidermal growth factor receptor (EGFR) is a receptor in the ErbB family, and is overexpressed in some cancer cells. Recent research has shown that, since clustering of the EGFR increases the possibility of its dimerization and activation, the dimerization state of the EGFR on the cell surface is important for the recognition of the EGFR. In case a bivalent inhibitor has an optimized linker length, the clusters of the EGFR could be recognized with high affinity and kinase activation, which depends on EGF, could be suppressed. Peptide 1, which is derived from the dimerization arm of the EGFR, has been found previously to inhibit autophosphorylation of the EGFR. In this study, bivalent ligands based on peptide 1 with linkers of poly(L-proline) or poly-[(glycine)4(L-serine)] have been designed and synthesized. Bivalent ligands with polyproline linkers could maintain the distance between the ligand moieties. The inhibitory activity of these bivalent ligands against EGFR autophosphorylation was measured and was found to increase as the linker enlarges up to a 15-mer proline linker. The inhibitory activity of a bivalent ligand 7b is significantly higher compared to the corresponding monomeric peptide 2a. This suggests that bivalent EGFR ligands with optimal and rigid linkers could recognize the clusters of the EGFR with higher affinity and suppress kinase activation involving EGF.
巻・号 66(11)
ページ 1083-1089
公開日 2018-1-1
DOI 10.1248/cpb.c18-00539
PMID 30381661
MeSH Dimerization Dose-Response Relationship, Drug Drug Design ErbB Receptors / antagonists & inhibitors* ErbB Receptors / metabolism Humans Ligands Molecular Structure Peptides, Cyclic / chemical synthesis Peptides, Cyclic / chemistry Peptides, Cyclic / pharmacology* Phosphorylation / drug effects Structure-Activity Relationship Tumor Cells, Cultured
IF 1.405
引用数 1
リソース情報
ヒト・動物細胞 A431(RCB0202)