Macrocyclization in the design of non-phosphorus-containing Grb2 SH2 domain-binding ligands

J Med Chem. 2004 Apr 8;47(8):2166-9. doi: 10.1021/jm030510e.


Macrocyclization from the phosphotyrosyl (pTyr) mimetic's beta-position has previously been shown to enhance Grb2 SH2 domain-binding affinity of phosphonate-based analogues. The current study examined the effects of such macrocyclization using a dicarboxymethyl-based pTyr mimetic. In extracellular assays affinity was enhanced approximately 5-fold relative to an open-chain congener. Enhancement was also observed in whole-cell assays examining blockade of Grb2 binding to the erbB-2 protein-tyrosine kinase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Binding Sites
  • Cell Line, Tumor
  • Cyclization
  • Drug Design
  • Enzyme-Linked Immunosorbent Assay
  • GRB2 Adaptor Protein
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Mimicry
  • Oligopeptides / chemistry*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Proteins / metabolism*
  • Receptor, ErbB-2 / metabolism
  • src Homology Domains*


  • 3-(2-amino-2-oxoethyl)-1,4,7-triaza-10-(4-(dicarboxymethyl)phenyl)-14-(1-naphthyl)-2,5,8-trioxo-6-pentamethylenecyclopentadecane-9-acetic acid
  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Ligands
  • Oligopeptides
  • Peptides, Cyclic
  • Proteins
  • Receptor, ErbB-2