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
DOI: 10.12677/hjmce.2024.123020, PDF,    国家自然科学基金支持
作者: 陈 卓, 堵桐弘, 吕遐师, 赖宜生*：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；李沛峰：中国药科大学基础医学与临床药学学院，江苏 南京
关键词: 蛋白酪氨酸磷酸酶；SHP2抑制剂；TNO155；生物活性；Protein Tyrosine Phosphatase； SHP2 Inhibitor； TNO155； Biological Activity
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。
Abstract: 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.
文章引用：陈卓, 堵桐弘, 吕遐师, 李沛峰, 赖宜生. 吡嗪类SHP2抑制剂的设计、合成及生物活性评价[J]. 药物化学, 2024, 12(3): 175-184. https://doi.org/10.12677/hjmce.2024.123020

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