Utilization of a beta-aminophosphotyrosyl mimetic in the design and synthesis of macrocyclic Grb2 SH2 domain-binding peptides.

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Lee K, Zhang M, Liu H, Yang D, Burke TR Jr

Utilization of a beta-aminophosphotyrosyl mimetic in the design and synthesis of macrocyclic Grb2 SH2 domain-binding peptides.

J Med Chem. 2003 Jun 19;46(13):2621-30.

PubMed ID

12801226 [ View in PubMed

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Abstract

Grb2 SH2 domains are protein-docking modules that exert important functions in both normal and pathogenic signal transduction processes. Development of synthetic Grb2 SH2 domain binding ligands is being pursued by several groups as potential new therapies for a variety of diseases, including certain cancers. In these efforts, macrocyclization has been successfully utilized to take advantage of preferential recognition by Grb2 SH2 domains of ligands in beta-bend conformations. Recent examples of this approach include olefin-metathesis-derived macrocycles that employ ring closure at the beta-position of key pTyr-mimicking residues. In the current study, a novel phosphatase-stable beta-amino-pTyr mimetic designated "Pmp(beta)" was utilized to prepare variants of previously reported olefin-metathesis-derived macrocycles. An initial set of simplified cyclic peptides lacking key naphthyl side chain functionality was first synthesized to determine optimum ring size, with results indicating that a four-unit ring-closing segment was appropriate. On the basis of these findings, macrolactamization was undertaken with a more highly functionalized, naphthyl-containing gamma-amino acid analogue. The resulting cyclic beta-amino peptide is the first of a new class of pTyr-mimetic-containing ligands that may have utility in the development of antagonists of both Grb2 SH2 domains and other pTyr-dependent signaling systems.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-[(10s,14s,18s)-18-(2-Amino-2-Oxoethyl)-14-(1-Naphthylmethyl)-8,17,20-Trioxo-7,16,19-Triazaspiro[5.14]Icos-11-En-10-Yl]Benzylphosphonic Acid	Growth factor receptor-bound protein 2	IC 50 (nM)	26	N/A	N/A	Details