肿瘤转移被认为与缺氧微环境关系密切，已证实缺氧可增强肿瘤细胞本身运动潜而促进转移。前期本课题针对缺氧微环境的研究，发现了全新抗肿瘤转移的靶蛋白WSB-1，并以此为切入点，通过基于WSB-1结构的虚拟筛选、活性测试获得了具有明确抗肿瘤转移活性的新型WSB-1抑制剂Dxw-W15。本项目拟进一步以其为基本骨架，综合运用电子等排、骨架迁跃、类药性分析、分子对接等技术对其进行合理设计，在有机合成、生物活性评价基础上，以期获得WSB-1抑制活性高、体内外抗肿瘤转移活性强的目标分子。并以其为分子探针，进一步阐明靶向WSB-1的抗肿瘤转移活性的独特机制。同时，通过NMR技术研究WSB-1蛋白与配体的结合模式，为两者的特异性结合提供直接证据。本课题的顺利实施将为证实WSB-1成为抗肿瘤转移的新靶标提供实验依据，同时对发现其他新型肿瘤转移调控蛋白及其小分子抑制剂的研究工作提供了借鉴。

Tumor metastasis is considered to be closely related to hypoxiic microenvironment, which has been confirmed to promote the tumor metastasis via directly enhancement of the potential motion ability of tumor cells themselves. Therefore, by targeting to hypoxic microenvironment, we have identified the E3 ubiquitin ligase WSB-1 as a key target protein for tumor metastasis, and successfully discovered a lead compounds Dxw-W15 as WSB-1 inhibitor explicitly with antitumor metastasis activities. Based on the basic skeleton of Dxw-W15, in this project, we will further perform the rational drug design and structural optimization of Dxw-W15 by the combined approaches of bioisosterism, skeleton hopping, drug-likeness analysis, molecular docking. After organic synthesis and biological evaluation of the terget compounds, we expect to obtain the highly active WSB-1 inhibitors with potent antitumor metastasis activities, which can be used as molecular probes to clarify the role of HIF-1-WSB-1 pathway in titumor metastasis and its exactly mechanism of WSB-1 inhibition. Meanwhile, the interaction mode between WSB-1 and the highly active WSB-1 inhibitors will be demonstrated by the NMR technology, to provide direct evidence that specific binding between each other. Therefore, the implementation of this project and the innovative found will provide the experimental basis to confirm the WSB-1 as novel an antitumor metastasis target under hypoxia. Also, this work can be of great reference significance for the discovery of other novel tumor metastasis regulatory proteins targeting hypoxia microenvironment, as well as their specific small molecular inhibitors.