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有机化学
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有机化学 ›› 2011, Vol. 31 ›› Issue (12): 2019-2033. 上一篇    下一篇

综述与进展

基于配体结构的Grb2-SH2抑制剂的结构优化：更高的活性、更少的电荷、更低的肽性

彭电1,2，智英1，薛婷1，高慧媛*,2，龙亚秋*,1   

  1. (1中国科学院上海药物研究所新药研究国家重点实验室 上海 201203)
    (2沈阳药科大学中药学院 沈阳 110016)
  • 收稿日期:2011-05-03 修回日期:2011-06-03 发布日期:2011-06-16
  • 通讯作者: 龙亚秋 E-mail:yqlong@mail.shcnc.ac.cn

The ligand-based structural optimization of Grb2-SH2 inhibitors: high affinity, low charge and reduced peptidic nature

Peng Dian1,2 Zhi Ying1 Xue Ting1 Gao Huiyuan*,2 Long Yaqiu*,1   

  1. (1 State Key Laboratory of Drug Research, Shanghai Institute of Medica, Chinese Academy of Sciences, Shanghai 201203)
    (2 School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016)
  • Received:2011-05-03 Revised:2011-06-03 Published:2011-06-16

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生长因子受体结合蛋白2 (Grb2)在致癌基因Ras活化的信号传导通路中起着关键作用, 目前被广泛认为是抗肿瘤药物设计的优秀靶标. 对Grb2-SH2抑制剂的研究进展进行了综述, 主要针对关键残基磷酸酪氨酸的高电荷性和多肽结构的低生物相容性两个缺陷, 基于天然配体与Grb2-SH2相互作用的结构特征, 围绕提高活性和简化结构开展的系统构效关系和合理结构优化研究, 为进一步开发磷酸酪氨酸介导的Grb2-SH2抑制剂成为新型抗肿瘤药物提供结构和理论基础.

关键词: 磷酸酪氨酸, Grb2-SH2抑制剂, 构效关系, 信号传导, 抗肿瘤

The growth factor receptor bound protein 2 (Grb2) is an intracellular adaptor protein. By its SH2 domain binding to the specific pTyr containing motif on the activated EGFR, Grb2 triggers the downstream activation of mitogenic Ras pathways which have been implicated in the etiology of certain breast cancers. So Grb2-SH2 has been recognized as an excellent target for the antitumor drug design. In this article, the re-cent progress of Grb2-SH2 inhibitors is reviewed, focused on the strategy to overcome the problems of the high charge and the low bioavailability endowed by the essential phosphotyrosine and the peptidic nature, respectively. The systematic structure-activity relationship study and the rational structural optimization were achieved based on the ligand-protein interaction to improve the potency and simplify the molecular structure, providing useful information for the future development of phosphotyrosine-mediated SH2 sig-naling inhibitors into antitumor agents.

Key words: phosphotyrosine, Grb2-SH2 inhibitor, structure-activity relationship, mitogenic ras pathway, anti-tumor drug