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

Ligand-Based Structural Optimization of Grb2-SH2 Inhibitors:High Affinity,Low Charge and Reduced Peptidic Nature

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.

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 recent 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.