吡嗪类SHP2抑制剂的设计、合成及生物活性评价  

Design, Synthesis and Biological Activity Evaluation of Pyrazine SHP2 Inhibitors

作　　者：陈卓 堵桐弘 吕遐师 李沛峰 赖宜生[1] 

机构地区：[1]中国药科大学新药研究中心,多靶标天然药物全国重点实验室,江苏 南京 [2]中国药科大学基础医学与临床药学学院,江苏 南京

出　　处：《药物化学》2024年第3期175-184,共10页Hans Journal of Medicinal Chemistry

摘　　要：SHP2是一个肿瘤治疗的潜在靶点。本文以TNO155为先导化合物,采用基于片段的药物设计策略,设计并合成三个系列共11个新型吡嗪类SHP2变构抑制剂,其结构均经1H-NMR和ESI-MS谱确证。采用荧光分析方法,通过替代底物DiFMUP的去磷酸化程度对目标化合物开展体外活性评价。结果表明,目标化合物对SHP2蛋白显示不同程度的抑制活性。其中2个化合物C-2和C-3的活性较为突出,值得进一步研究。Eleven novel pyrazine SHP2 allosteric inhibitors were designed and synthesized in three series based on TNO155 of Novartis, drug design strategy based on fragments and molecular docking technology of computer-aided drug design. Their structures were confirmed by 1H-NMR and ESI-MS spectra. The in vitro activity of DiFMUP was evaluated by fluorescence analysis. The results showed that the target compounds showed different degrees of inhibitory activity on SHP2. Among them, two compounds, C-2 and C-3, have outstanding activity and deserve further study.

关 键 词：蛋白酪氨酸磷酸酶 SHP2抑制剂 TNO155 生物活性 

分 类 号：R28[医药卫生—中药学]