CYCLIC PEPTIDE INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASE P85 SH2 DOMAIN BINDING

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 mu M) < phosphonodifluoromethyl phenylalanine (F(2)Pmp, ID50 = 2.2 mu M) < pTyr (ID50 = 1.0 mu M), With Xxx = Tyr being inactive (ID50 > 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. (C) 1994 Academic Press, Inc.