基于代谢潜能挖掘与靶点追踪的海洋微生物抗肿瘤先导化合物发现和优化

肿瘤治疗是国家重大需求，靶向药物是目前抗肿瘤药物研究的重点。海洋微生物已经成为抗肿瘤先导化合物发现的新资源，但面临着基因沉默严重、结构复杂、靶点确定难度大的瓶颈问题。瞄准创制新结构、新靶点、新机制海洋药物的目标，针对如何高效获得新型靶向抗肿瘤先导化合物这一关键科学问题，本项目基于沉默基因激活新技术挖掘海洋微生物的代谢潜能，提高海洋天然产物的结构多样性，拓展先导化合物发现的源头；利用抗肿瘤前沿靶点筛选体系以及所构建的靶点高表达肿瘤细胞株，采取表型-靶点相结合的模式快速追踪确认活性化合物及其作用靶点；并通过对天然先导化合物的构效关系探讨优化其结构，提高成药性，以期获得新型候选药物分子。本项目对于深度开发利用海洋生物资源，推动具有自主知识产权的海洋创新药物研制具有重要意义。

Tumor treatment is one of the most urgent demands by public healthcare. Tumor-targeted drugs development is playing pivotal roles in nowadays anti-tumor research. Within the key scientific scope of discovery of drug leads with novel structures, new anti-tumor targets and new anti-tumor mechanisms, this project will focus on how to efficiently obtain lead structures from the important natural product resource of marine-derived microorganism, which could be divided into three parts: 1) activation of silent genes that related to the secondary metabolites’ biosynthesis in marine-derived microorganisms and improvement of the structural diversity of marine natural products ; 2) construction of tumor cell lines with high-expression of various targets related to tumor therapy, and employing phenotypic-target combination method as screening strategies for tracking and targeting new anti-tumor leading compounds; 3) structure optimization of the leading compounds based on structure-activity relationship research, with regarding to obtain new drug candidates. This project is of great significance for the in-depth development and utilization of marine biological resources and the promotion of marine innovative drugs with independent intellectual property rights.