DNA methyltransferase 1（DNMT1）是第一个被发现的DNA甲基转移酶，其异常与多种肿瘤的发生发展密切相关。因此，针对其催化机制及药物发现的研究是目前表观遗传研究的重要内容。然而，目前DNMT1催化DNA甲基化的机制仍没有被阐明, 新的关键性调控区域有待发现。此外，现有的DNMT1抑制剂选择性差、毒副作用大。本项目将基于前期已发现的DNMT1新的关键性动态调控区域研究其调控机制，阐明其对DNMT1正常行使功能的重要性；同时基于前期获得的目前选择性最好的DNMT1抑制剂，开展针对自主发现的动态调控区域的个性化先导化合物发现研究。本项目将不仅揭示DNMT1新的动态调控机制，同时为DNMT1特异性抑制剂的开发提供理论和技术支撑，为针对多种肿瘤的治疗提供新的个性化药物先导结构。最终，拟获得DNMT1先导化合物1-2个，发表SCI论文2-3篇，申请专利1-2项。

DNA methylation is catalyzed by DNA methyltransferases (DNMTs) and among which DNMT1 is first discovered. DNMT1 plays an important role in cancer initiation and progression. Catalytic mechanism studies and drug discovery of DNMT1 are currently important topics in the field of epigenetics. However, the questions that how the DNA substrate specifically catalyzed by DNMT1 are left to be settled and the new regulatory regions of DNMT1 are to be founded. Moreover, a number of DNMTs inhibitors have been reported but most of them suffer from the lack of specificity and have toxic side-effects . In this project, we aim to provide molecular insights into the dynamic regulatory mechanism of the functional conformation changes of DNMT1 and show it important role for DNMT1 to function. In terms of compound discovery, we have already obtained novel DNMT1 inhibitor, which has the best selectivity among DNMT1 inhibitors. Based on this condition, we will focus on the new regulatory regions of DNMT1 to design and obtain a series of novel personalized DNMT1 leading compounds. Overall, this project will not only provide novel molecular insights into dynamic regulation of DNMT1, but also lay the foundation for further development of specific DNMT1 small molecule inhibitors. Moreover, we'll provide novel personalized leading scaffolds for different kinds of cancers therapy. Finally, we are anticipating to obtain 1-2 DNMT1 lead compounds，2-3 SCI papers and 1-2 patents applications.