Cyclic peptide inhibitors of phosphatidylinositol 3-kinase p85 SH2 domain binding

Abstract

Cyclic hexameric peptides based on the amino acid sequence “Gly-Xxx-Val- Pro-Met-Leu”, where Xxx is either phosphotyrosyl (pTyr) residue or a hydrolytically stable pTyr mimetic, were examined for their ability to bind to the C-terminal SH2 domain of the p85 phosphoinositol 3-kinase (PI 3- kinase). The cyclic peptides retained significant binding affinity relative to their linear counterparts. Potency varied depending on Xxx in the order: phosphonomethyl phenylalanine (Pmp, ID50 = 5.2 μM) < phosphonodifluoromethyl phenylalanine (F2Pmp, ID50 = 2.2 μM) 500 M). Greatly reduced potency was observed when Xxx was of the unnatural D-configuration. The cyclic peptides represent conformationally constrained ligands which should be useful in the development of p85 SH2 domain-directed inhibitors. © Academic Press, Inc.