Development of a phosphatase-stable phosphotyrosyl mimetic suitably protected for the synthesis of high-affinity Grb2 SH2 domain-binding ligands

Bioorg Med Chem Lett. 2002 Oct 7;12(19):2781-4. doi: 10.1016/s0960-894x(02)00527-9.

Abstract

Synthesis of (2R)-2-carboxymethyl-3-(4-(phosphonomethyl)phenyl) proprionic acid (5) in tert-butyl-protected form (6) and its use for the preparation of a Grb2 SH2 domain-directed tripeptide (8a) is reported. In extracellular ELISA-based assays, 8a exhibits potent Grb2 SH2 domain binding affinity (IC(50)=8 nM). Against cultures of MDA-MB-453 breast cancer cells, which over-express erbB-2 tyrosine kinase, 8a is also antimitogenic at concentrations equivalent to those required to inhibit intracellular association of Grb2 protein with phosphorylated p185(erbB-2) protein (IC(50)=8 microM). Analogue 6 may be useful for the preparation of a variety of phosphatase-stable SH2 domain-directed ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / pathology
  • Cell Membrane Permeability / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • GRB2 Adaptor Protein
  • Humans
  • Indicators and Reagents
  • Ligands
  • Molecular Mimicry
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphotyrosine / chemistry*
  • Proteins / drug effects*
  • Receptor, ErbB-2 / drug effects
  • Receptor, ErbB-2 / metabolism
  • Tumor Cells, Cultured
  • src Homology Domains / drug effects*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Indicators and Reagents
  • Ligands
  • Proteins
  • Phosphotyrosine
  • Receptor, ErbB-2
  • Phosphoric Monoester Hydrolases