基于STAT3信号通路探究抗肿瘤先导化合物WJ-13的作用机制与结构优化

项目名称： 基于STAT3信号通路探究抗肿瘤先导化合物WJ-13的作用机制与结构优化

项目编号： No.81473133

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李敏一

作者单位： 暨南大学

项目金额： 65万元

中文摘要： 我们前期研究的结果表明来源于红树植物角果木的dolabrane型二萜化合物WJ-13在5-10μM的浓度下能够显著地降低人源黑色素瘤A2058细胞中被活化的STAT3-STAT3蛋白二聚体的水平，并且呈现出良好的时间和剂量依赖关系。WJ-13主要是诱导了磷酸酯酶对被活化的STAT3-STAT3蛋白二聚体的去磷酸化作用，使得该二聚体得以快速降解。文献与专利检索证实WJ-13为新结构类型的STAT3信号通路小分子抑制剂。因此，本申请项目拟在拓展东南亚红树植物资源的基础上，采用液相-质谱联用等现代分析手段寻找WJ-13高含量的角果木属红树植物，并对该目标化合物进行克级以上量的累积。然后基于STAT3信号通路，在深入探究WJ-13确切作用机制的基础上，结合计算机辅助药物设计对它进行结构优化，以期获得高活性化合物，并经由小鼠在体模型的药理药效学评价发现药物先导结构。

中文关键词： STAT3信号通路；抗肿瘤活性；先导化合物；作用机制；结构优化

英文摘要： Our previous research achievements revealed that a new dolabrane-type diterpenoid compound named WJ-13, which was obtained from the mangrove Ceriops tagal, can significantly decrease the level of the activated STAT3-STAT3 protein dimmer with time- and dose-dependent manner in human melanoma A2058 cells at the concentrations of 5-10 μM. WJ-13 mainly induced the dephosphorylation of the activated STAT3-STAT3 protein dimmer via phosphatase and resulted in the rapid degradation of this protein dimmer. Scientific document and patent retrieval demonstrated that WJ-13 is a new structure type of small molecule inhibitors of the STAT3 signaling pathway. Based on expanding resources of southeast Asian mangrove plants, this proposal aims to utilize modern analytic techniques, including liquid chromatography/mass spectrometry, etc, to search for WJ-13 high content mangrove plants of the genus Ceriops and then accumulated gram-scale of WJ-13 from the objective plants. Moreover, the exact action mechanism of WJ-13 will be deeply investigated based on STAT3 signaling pathway and computer-aided drug design will be employed for structure optimization of WJ-13 to gain highly active derivatives. Afterwards, pharmacological and pharmacodynamic evaluation on mouse model will be applied to find drug leads.

英文关键词： STAT3 signaling pathway;Antitumor activity;Leading compound;Action mechanism;Structure Opimization