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 β-bend conformations. Recent examples of this approach include olefin-metathesis-derived macrocycles that employ ring closure at the β-position of key pTyr-mimicking residues. In the current study, a novel phosphatase-stable β-amino-pTyr mimetic designated "Pmpβ" 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 γ-amino acid analogue. The resulting cyclic β-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.
Original language | English |
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Pages (from-to) | 2621-2630 |
Number of pages | 10 |
Journal | Journal of Medicinal Chemistry |
Volume | 46 |
Issue number | 13 |
DOIs | |
State | Published - 19 Jun 2003 |