基于靶向抑制未折叠蛋白反应(UPR)的抗肿瘤活性化合物发现与作用机制研究

癌症在我国已成首位死因，开发有效抗肿瘤药物极为迫切。多靶向药理学逐渐成为现在药物研究和开发的重要策略。UPR整体信号网络作为多种肿瘤共同的适应性应激机制，在肿瘤的发生、发展以及耐药方面有着非常重要的作用，是良好的多靶向药理学研究模型。本项目拟针对UPR信号网络，探索开发新型、低毒、高效创新抗肿瘤药物的可行性。通过建立指针细胞水平UPR激活状态的多个细胞筛选模型，发现潜在抑制UPR信号网络的候选化合物；通过细胞水平评价候选化合物对肿瘤细胞生长、细胞凋亡以及细胞周期等的影响，并研究其作用机制与UPR抑制相关性；进而在动物水平评估UPR的抑制剂单独使用以及与抗肿瘤药物联合使用的抗肿瘤活性。与此同时，我们也将通过研究候选化合物调控UPR的作用机制，探讨内在的UPR调控新机制。二者相相互结合促进，为开发有效抗肿瘤药物提供新的研究策略与先导化合物。

Cancer has become the leading cause of death in our country. Effective anti-cancer drug treatment is extremely urgent. Polypharmacology is now becoming an important drug development strategy. UPR signaling network as the tumors common stress adaptation mechanism, has a very important role in the occurrence, development and drug resistance of tumors. So based on polypharmacology strategy, Here, we propose to target UPR signaling network for the discovery of innovative anticancer drugs with low toxicity and high efficiency. Multiple cellular UPR activation screening models are established, High-throughput screened (HTS), and potential candidate compounds inhibiting the UPR signaling networks would be found. Then, the effect of candidate compounds on tumor cells growth, apoptosis and cell cycle will be evaluated in single or combination treatment. Furthermore, the relationship between UPR inhibition and the anti-cancer effect will be evaluated. At last, the anti-cancer activity of UPR inhibitor on animal model will be evaluated to in single or combinated with anti-cancer drug treatment. On the other hand, we will also study the mechanism of compounds inhibiting UPR, and to explore new inherent UPR regulation mechanisms. All the work would lay the foundation for anti-cancer new research strategies and lead compounds.