上皮细胞-间充质细胞转化（EMT）引起的肿瘤转移是导致肿瘤病人死亡的最主要原因。其中E-cadherin表达量减少是EMT转化的标志性现象，并且Wnt /β-catenin信号通路在EMT过程中扮演十分重要的角色。研究发现组蛋白去乙酰化酶抑制剂（HDACi）可上调E-cadherin表达抑制EMT过程，而Wnt /β-catenin信号通路中胸腺嘧啶DNA糖基化酶（TDG）参与形成转录复合体调控EMT相关蛋白表达，因此协同抑制HDAC和TDG可以更有效调控EMT过程。申请者前期发现的N-双取代异羟肟酸HDACi具有一定的抗肿瘤转移功能，本项目拟在其结构基础上引入TDG抑制剂的药效团，设计合成新型具有抗肿瘤转移功能的HDAC/TDG双靶点抑制剂，开展结构优化和构效关系研究，通过优选活性化合物的体内药效评价，最终得到具有显著抗肿瘤转移作用的先导化合物。为抗肿瘤转移双靶点抑制剂开发提供新的方向。

Tumor metastasis is the key factor for cancer death, Epithelial-mesenchymal transition (EMT) is closely related to the process of tumor metastasis. The decreased expression of E-cadherin is often considered as the symbol of EMT process, Wnt /β-catenin signaling pathway plays a crucial role in EMT. HDACi can reverse EMT through increasing the expression of E-cadherin, TDG can regulate the exprssion of EMT related protein by forming transcription complex, so synergistic inhibition of HDAC and TDG may regulate EMT more effectively. Applicant previously found one series of N-bissubstituted hydroxamate HDACi, which have certain anti-metastasis effects. In this project, we insert pharmacophore of TDG inhibitors into HDACi, got compouds which can target HDAC and TDG at the same time, then study on structural optimization and structure-activity relationship. Finally, the new drug candidates against tumor metastasis can be found by in vivo evaluation on active compounds. Which can provide a new direction for researching dual-target inhibitors with anti-metastasis activities.