Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3'-substituted tyrosine derivatives

Journal of Medicinal Chemistry
Yan-Li SongY Q Long

Abstract

The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. An impressive number of synthetic Grb2-SH2 domain inhibitors have been identified; however, clinical agents operating by this mechanism are lacking, due in part to the unique requirement of anionic phosphate-mimicking functionality for high SH2 domain-binding affinity or the extended peptide nature of most inhibitors. In the current study, a new binding motif was successfully developed by the incorporation of 3'-substituted tyrosine derivatives into a simplified nonphosphorylated cyclic pentapeptide scaffold (4), which resulted in high affinity Grb2-SH2 inhibitors without any phosphotyrosine or phosphotyrosine mimetics. The new L-amino acid analogues bearing an additional nitro, amino, hydroxy, methoxy or carboxy group at the 3'-position of the phenol ring of tyrosine were prepared in an orthogonally protected form suitable for solid-phase peptide synthesis using Fmoc protocols. The incorporation of these residues into cyclic peptides composed of a five-amino acid sequence motif, Xx(1)-Leu-(3'-substituted-Tyr)-Ac6c-Asn, provided a brand new class of nonphospho...Continue Reading

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Citations

Jan 16, 2009·Blood·Frank BreitenbuecherThomas Fischer
Apr 14, 2009·Journal of Molecular Biology·Andrew SeverinAmy H Andreotti
Jul 16, 2008·Expert Opinion on Therapeutic Targets·Alessio GiubellinoDonald P Bottaro
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Nov 30, 2019·Organic & Biomolecular Chemistry·Robert A Cerulli, Joshua A Kritzer
Oct 16, 2008·The Journal of Organic Chemistry·Xiaojun HanGene M Dubowchik
Jan 14, 2012·ACS Chemical Biology·Katsunori TanakaKoichi Fukase

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