癌基因NRAS的异常激活是黑色素瘤发生发展的关键因素。由于以NRAS蛋白为靶点的药物研发屡遭失败，通过NRAS基因表达调控达到抗肿瘤目的成为重要途径。NRAS mRNA 5′-UTR上保守的G-四链体被证明是调控NRAS基因翻译的“分子开关”，因此，以该G-四链体为靶点发展基于翻译调控的新型抗黑色素瘤药物研究具有重要意义。我们前期基于新型探针方法成功筛选得到能特异性结合并稳定该G-四链体的小分子化合物a1，并发现化合物a1可下调NRAS基因表达、抑制黑色素瘤细胞的生长。本项目将在此基础上，以a1为先导结构，通过设计、合成、筛选与评价，获得特异性靶向该G-四链体的优良配体，总结构效关系，揭示化合物与靶点相互作用规律，探究化合物对NRAS基因翻译及相关通路的调控作用及分子机制，发现新型抗黑色素瘤先导化合物，为基于癌基因NRAS翻译调控的抗癌药物研究新策略提供重要理论及实验依据。

Abnormal activation of NRAS protein is a key role for the development of melanoma. Current research and development of drugs inhibiting the NRAS protein have been failing to achieve ideal results. So, inhibiting the activity of NRAS protein by regulation of NRAS translation is an important way for developing molecular targeted cancer therapeutics. Conservative G-quadruplex in NRAS mRNA 5′-UTR region is the molecular switch of NRAS translation, research on anti-melanoma drugs based on NRAS G-quadruplex is very important. According to the activity screening system created by our lab, we have found compound a1 that could stabilize the NRAS mRNA G-quadruplex, down regulate NRAS expression, and inhibit melanoma cell growth. In this research, on the basis of compound a1, we will design, synthesize and identify some new small molecules that could specifically bind NRAS G-quadruplex, summarize the structure-function relationship, and further study the molecular mechanism of their effect on NRAS translation and NRAS relative signal path way. This project might provide a more solid theoretical and experimental basis and new lead compounds for the establishment of new therapy strategy and the development of new anti-melanoma drugs.