title: Development of l-3-aminotyrosine suitably protected for the synthesis of a novel nonphosphorylated hexapeptide with low-nanomolar Grb2-SH2 domain-binding affinity.
abstract: Synthesis of orthogonally protected (2S)-2-amino-3-(3-amino-4-hydroxy-phenyl)-propionic acid (10) suitable for solid phase peptide synthesis and its first use for the preparation of nonphosphorylated Grb2-SH2 domain antagonists (4a-c) are reported. The 3-aminotyrosine containing sulfoxide-cyclized hexapeptide (4b) exhibited potent Grb2-SH2 domain binding affinity with IC50 = 50 nM, which represents the highest affinity yet reported for a peptide inhibitor against Grb2-SH2 domain with only 6 residues free of phosphotyrosine or phosphotyrosine mimics. This potent small peptidomimetic 4b may be representative of a new class of therapeutically relevant Grb2-SH2 domain-directed agents, and acts as a chemotherapeutic lead for the treatment of erbB2-related cancers.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Song
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D036103:Nanotechnology / Q000379:methods*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D009842:Oligopeptides; C019253:3-aminotyrosine; D014443:Tyrosine