研究表明小G蛋白Ral介导的信号通路在Ras驱动的癌症中起核心作用，有望成为抗癌药物的新靶点。申请人前期在Nature杂志报道了首个靶向失活状态Ral-GDP的别构抑制剂BQU57，并使用核磁共振等技术研究了其作用机制。同时我们还通过分子建模和虚拟筛选发现了首个靶向活化状态Ral-GTP与其效应蛋白RalBP1之间蛋白-蛋白相互作用的正构抑制剂MAT15。我们拟以BQU57和MAT15作为先导化合物开展结构优化，以期获得两种机制各异但又互为补充的活性更强的Ral抑制剂，进而分别利用Ral别构和正构抑制剂作为分子探针，在蛋白、细胞和动物水平对Ral的生物学功能进行交叉验证，通过研究蛋白构象变化对上下游信号分子的影响阐明Ral信号通路介导Ras促肿瘤信号的分子机制，并结合基因技术验证Ral信号通路在Ras突变驱动的非小细胞肺癌发生发展中的核心作用，为研制靶向Ral信号通路的抗肿瘤药物奠定基础。

Previous studies suggest that Ral small GTPase plays critical role in Ras-driven human cancers and is a potential target for anti-cancer drug development. Recently we reported the discovery of the first small molecule allosteric inhibitor of Ral, BQU57, which showed considerable antitumor activity against NSCLC. Using molecular modeling and virtual screening approaches, we have also discovered MAT15, an orthosteric inhibitor of Ral that targets the protein-protein interaction between active GTP-bound Ral and its effectors. Using BQU57 and MAT15 as lead compounds, we will carry out structure optimization in order to develop more potent and specific inhibitors of Ral. Using the two type of Ral inhibitors which complements each other in mechanism of inhibition, we will set out to probe the mechanism of Ras-mediated Ral activation in NSCLC as well as the mechanism of antitumor activity of Ral inhibitors. We will also use the inhibitors to validate Ral as a potential therapeutic target in NSCLC. Our study will lay the foundation for the development of novel cancer therapeutics targeting the Ral pathway.