基于“SuFEx化学蛋白质组学”研究吴茱萸碱抑制STAT-3信号通路的靶点

信号转导和转录激活因子-3（STAT-3）信号通路在多种肿瘤细胞中持续性激活，是抗癌药物研发的重要信号通路。本团队前期研究发现，吴茱萸碱可以通过多种途径抑制STAT-3信号通路的激活，但是直接作用靶标尚未确认，限制了其基于STAT-3信号通路的活性优化和成药性改善。针对该问题，本项目拟设计一系列吴茱萸碱氟磺酸酯探针，将新型“点击化学”六价硫氟交换反应（SuFEx）用于化学蛋白质组学研究，以寻找吴茱萸碱抑制STAT-3信号通路的直接靶标，结合计算机模拟和结构生物学技术，期望揭示吴茱萸碱抑制STAT-3信号通路的结构基础。

Signal Transducer and Activator of Transcription 3 (STAT-3) signal pathway is persistent activated in many kinds of tumor cells, thus it is a very important signal pathway in the development of anti-tumor drugs. Our team previously discovered that evodiamine could inhibit the activation of STAT-3 signal pathway through several possible mechanisms. However, the direct targets have not been identified, which may obstruct the optimization of activity and druggability of evodiamine. With regard to the above issue, this project focuses on designing a series of evodiamine fluorosulfate probes to search for the direct targets of evodiamine based on the novel “sulfur (VI) fluoride exchange chemical proteomics”. Furthermore, by applying computer simulation and structural biology technologies, this project will try to reveal the structural basis of evodiamine-induced inhibition of STAT-3 signal pathway.