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Potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics

  1. Author:
    Li, P.
    Zhang, M. C.
    Long, Y. Q.
    Peach, M. L.
    Liu, H. P.
    Yang, D. J.
    Nicklaus, M.
    Roller, P. P.

  2. Author Address

    NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA Roller PP NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Bioorganic & Medicinal Chemistry Letters
    1. 13
    2. 13
    3. Pages: 2173-2177
  4. Type of Article: Article
  1. Abstract:

    Development of Grb2-SH2 domain antagonists is an effective approach to inhibit the growth of malignant cells by modulating Grb2-related Ras signaling. We report here potent Grb2-SH2 domain antagonists that do not rely on phosphotyrosine or its mimics. These non-phosphorylated antagonists were developed and further modified by constraining the backbone conformation and optimizing amino acid side chains of a phage library-derived peptide, G1TE. After extensive SAR studies and structural optimization, non-phosphorylated peptide 12 was discovered with an IC50 of 75 nM. This potent peptidomimetic provides a novel template for the development of non-pTyr containing Grb2-SH2 domain antagonists and acts as a chemotherapeutic lead for the treatment of erbB2-related cancer. (C) 2003 Elsevier Science Ltd. All rights reserved.

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