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 microM) < phosphonodifluoromethyl phenylalanine (F2Pmp, ID50 = 2.2 microM) < pTyr (ID50 = 1.0 microM), 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.
Laboratory of Medicinal Chemistry, NCI, National Institutes of Health, Bethesda, MD 20892.
T R
TR
Burke
M
M
Nomizu
A
A
Otaka
M S
MS
Smyth
P P
PP
Roller
R D
RD
Case
G
G
Wolf
S E
SE
Shoelson
D000595:Amino Acid Sequence; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)