基于癌基因c-myc转录调控的新型抗耐药非小细胞肺癌的先导化合物发现及作用机制研究

Drug resistant Non-Small Cell Lung Cancer (NSCLC) is an important problem for cancer clinical treatment, because of their pathogenesis is complicated and the mortality is high. Abnormal activation of c-myc is a key role for the development of NSCLC, and the G-quadruplex in c-myc promoter region is the molecular switch of c-myc translation. So, try to avoid the protein target for its mutable, research on anti-drug resistant NSCLC based on c-myc G-quadruplex is a new strategy. According to the activity screening, we found compound YA12 that could to stabilize the c-myc G-quadruplex, down regulate of c-myc expression, and inhibit drug resistant NSCLC cell growth. In this research, on the basis of active compound YA12, we will design, synthesize and identify some new small molecules that could specifically bind c-myc G-quadruplex, summarize the structure-function relationship, and further study the molecular mechanism of the regulation of c-myc translation and relative signal path way, like PI3K/AKT/mTOR path way and MAPK/EKR 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-drug resistant NSCLC drugs.

非小细胞肺癌耐药现象因其机制复杂、死亡率高成为临床治疗的难题，癌基因c-myc的异常激活是肺癌发生发展的关键因素，且c-myc基因启动子区的G-四链体是调控基因转录的“分子开关”。故避开易突变的蛋白靶点，以c-myc G-四链体为靶点，发展调控c-myc转录的新药研发策略成为控制耐药非小细胞肺癌的新途径。我们前期筛选到特异性结合该G-四链体的小分子YA12，并发现YA12可下调c-myc基因转录和表达、抑制耐药肺癌细胞的生长。本项目将在此基础上，以YA12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-四链体的小分子，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c-myc基因转录及PI3K/AKT/mTOR和MAPK/EKR等相关通路的调控作用及分子机制，发现新型抗耐药非小细胞肺癌的先导化合物，为基于癌基因c-myc转录调控的抗癌药物研究新策略提供理论及实验依据。

非小细胞肺癌耐药现象因其机制复杂、死亡率高成为临床治疗的难题，癌基因c-myc的异常激活是肺癌发生发展的关键因素，且c-myc基因启动子区的G-四链体是调控基因转录的“分子开关”。故避开易突变的蛋白靶点，以c-myc G-四链体为靶点，发展调控c-myc转录的新药研发策略成为控制耐药非小细胞肺癌的新途径。本项目以天然产物为先导结构，通过设计、合成、筛选与评价，获得特异性靶向该G-四链体的小分子，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c-myc基因转录及相关通路的调控作用及分子机制，发现新型抗耐药非小细胞癌的先导化合物，为基于癌基因c-myc转录调控的抗癌药物研究新策略提供理论及实验依据。