不依赖磷酸酪氨酸模拟物的强效Grb2-SH2结构域拮抗剂。
Potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics.
作者信息
Li Peng, Zhang Manchao, Long Ya Qiu, Peach Megan L, Liu Hongpeng, Yang Dajun, Nicklaus Marc, Roller Peter P
机构信息
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, 21702, Frederick, MD, USA.
出版信息
Bioorg Med Chem Lett. 2003 Jul 7;13(13):2173-7. doi: 10.1016/s0960-894x(03)00385-8.
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 IC(50) 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.
开发Grb2-SH2结构域拮抗剂是通过调节Grb2相关的Ras信号传导来抑制恶性细胞生长的有效方法。我们在此报告了不依赖磷酸酪氨酸或其模拟物的强效Grb2-SH2结构域拮抗剂。这些非磷酸化拮抗剂是通过限制噬菌体文库衍生肽G1TE的主链构象并优化氨基酸侧链而开发并进一步修饰的。经过广泛的构效关系研究和结构优化，发现了非磷酸化肽12，其IC(50)为75 nM。这种强效拟肽为开发不含磷酸酪氨酸的Grb2-SH2结构域拮抗剂提供了一种新模板，并作为治疗erbB2相关癌症的化疗先导物。
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