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A novel macrocyclic tetrapeptide mimetic that exhibits low- picomolar Grb2 SH2 domain-binding affinity

  1. Author:
    Shi, Z. D.
    Lee, K.
    Liu, H. P.
    Zhang, M. C.
    Roberts, L. R.
    Worthy, K. M.
    Fivash, M. J.
    Fisher, R. J.
    Yang, D. J.
    Burke, T. R.

  2. Author Address

    NCI, CCR, Med Chem Lab, NIH, Frederick, MD 21702 USA NCI, CCR, Med Chem Lab, NIH, Frederick, MD 21702 USA Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA Burke TR NCI, CCR, Med Chem Lab, NIH, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Biochemical and Biophysical Research Communications
    1. 310
    2. 2
    3. Pages: 378-383
  4. Type of Article: Article
  1. Abstract:

    The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that participates in the signaling of numerous oncogenic growth factor receptor protein- tyrosine kinases (PTKs). Presented herein is a 5-methylindolyl- containing macrocyclic tetrapeptide mimetic (5) that binds to Grb2 SH2 domain protein with K-d = 75 pM. This represents the highest affinity yet reported for a synthetic inhibitor against any SH2 domain. In whole cell assays this novel analogue is able to effectively block the association of Grb2 to cognate cytoplasmic erbB-2 at IC50 < 10nM without prodrug derivatization or the addition of carrier peptide motifs. Anti- mitogenic effects against erbB-2-dependent breast cancers are achieved at non-cytotoxic concentrations (IC50 = 0.6 muM). Macrocycle 5 may be representative of a new class of therapeutically relevant Grb2 SH2 domain-directed agents. Published by Elsevier Inc.

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