Development of l-3-aminotyrosine suitably protected for the synthesis of a novel nonphosphorylated hexapeptide with low-nanomolar Grb2-SH2 domain-binding affinity

Bioorg Med Chem Lett. 2004 Jun 21;14(12):3205-8. doi: 10.1016/j.bmcl.2004.03.103.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • GRB2 Adaptor Protein
  • Nanotechnology / methods*
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / metabolism
  • Phosphorylation
  • Protein Binding / physiology
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis*
  • Tyrosine / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Oligopeptides
  • 3-aminotyrosine
  • Tyrosine