Synthesis and utilization of chiral alpha-methylated alpha-amino acids with a carboxyalkyl side chain in the design of novel Grb2-SH2 peptide inhibitors free of phosphotyrosine

J Med Chem. 2008 Oct 23;51(20):6371-80. doi: 10.1021/jm800487r. Epub 2008 Sep 27.


The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. To improve the potency and bioavailability of the Grb2-SH2 inhibitors, the chiral alpha-methyl-alpha-carboxyalkyl amino acid [(alpha-Me)Aa] was designed to cover dual structural and functional features separately contributed by 1-aminocyclohexanecarboxylic acid (Ac6c) and alpha-aminoadipic acid (Adi) in position Y + 1. The enantiopure l(or D)-(alpha-Me)Aa bearing various chain length carboxylalkyl side chain was conveniently synthesized by an optimized oxazolidinone methodology. The incorporation of (S)-(alpha-Me)Aa into the non-pTyr-containing peptide framework with a 5-amino acid sequence binding motif of X (-2)-Leu-(3'-substituted-Tyr) (0)-X (+1)-Asn really improved the inhibitory activity, affording potent (R)-sulfoxide-bridged cyclic and an open-chain series of pentapeptide inhibitors of Grb2-SH2 domain (IC 50 = 1.1-5.8 microM). More significantly, these (alpha-Me)Aa incorporated peptide inhibitors showed excellent activities in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with low micromolar IC 50 values, owing to the reduced peptidic nature and absence of pTyr or pTyr mimetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Carboxylic Acids / chemistry*
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Design*
  • GRB2 Adaptor Protein / antagonists & inhibitors*
  • GRB2 Adaptor Protein / metabolism
  • Humans
  • Methylation
  • Neoplasms / pathology
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Phosphorylation
  • Stereoisomerism
  • Structure-Activity Relationship
  • src Homology Domains*


  • Amino Acids
  • Carboxylic Acids
  • GRB2 Adaptor Protein
  • Peptides