分子靶向药物的临床应用，充分证明通过肿瘤分子机制研究寻找有治疗价值的分子靶标并开发靶向肿瘤治疗药物潜能巨大。近年发现，哺乳动物雷帕霉素靶蛋白（mTOR）信号通路对细胞自噬发挥了最直接的调控作用，其过度活化与肿瘤的发生、发展密切相关，是肿瘤治疗的分子靶点。我们在前期工作中对一叶萩型生物碱类化合物进行了系统的活性研究，观察到此类化合物可抑制肿瘤细胞生长，并通过抑制mTOR活性诱导自噬性凋亡发生；同时发现，该类化合物抗肿瘤活性存在立体选择性差异。本项目拟在前期工作基础上，进一步对一叶萩型生物碱类成分进行分离和鉴定，评价和研究该类化合物抑制 mTOR活性和抗肿瘤作用，并重点观察该类化合物与mTOR的相互作用（结合位点、结合模式及结合效应）和构效关系，弄清其对mTOR等相关自噬信号转导通路的调控机制，为研究和开发靶点清楚、机制明确的新型抗肿瘤药物提供科学依据。

The clinical application of molecular targeted drugs fully proved that it has great potential to find molecular targets of therapeutic value and develop drugs of targeted cancer therapy through the research on the mechanism of tumor molecular. In recent years, it has been found that the signaling pathway of the mammalian target of rapamycin (mTOR) plays the most direct role in regulating autophagy, that its excessive activation is closely related with the occurrence and development of the tumor, and that it is the molecular target for cancer treatment. Through the preliminary systematic research on the activity of alkaloid compounds from securinega suffruticosa, we found that the hagi-alkaloid compounds can inhibit the growth of tumor cells and induce the autophagic apoptosis by inhibiting mTOR activity. It was also found that such compounds are stereoselectively different in the anti-tumor activity. Based on the previous work, the project is planned to further separate and identify the alkaloids from Securinega suffruticosa, evaluate and study the antitumor effect of these compounds and their role in inhibiting mTOR activity. The research will mainly focus on observing the interaction (binding sites, the binding mode and binding effect) and structure-activity relationship between these compounds and mTOR, and clarify the regulatory mechanism of the mTOR and other autophagy signal transduction pathway so as to provide the scientific basis for the research and development of new anticancer drugs with clear target and definite mechanism.