针对DNA甲基转移酶1的药物发现与化学干预研究

DNA methylation is catalyzed and maintained by DNA methyltransferases (DNMTs). DNMT1 is one important enzyme of DNMTs and plays an important role in cancer initiation and progression, thus it has been proved to be attractive targets in cancer chemotherapy. A number of DNMTs inhibitors have been reported but most of them are instable and have toxic side-effects and suffer from the lack of specificity. We have already established multiple compound screening and evaluation platforms targeting DNMT1 and other methyltranferases. By using these platforms, we have already obtained novel and selective DNMT1 inhibitors. In this project, based on the above conditions, we will combine structure-activity relationship analysis, rational combinatorial library design, structure optimization and ADME/Tox prediction to accelerate design and obtain a series of novel selective DNMT1 leading compounds with high inhibitory potency and drug-likeness. Then, we will employ the newly developed DNMT1 compound as a chemical probe and combine with the DNMT1 structure-function relationship to discovery and design novel DNMT1 leading compounds, and then to explore the mechanism in enzyme, cancer cells and animal models. Finally, all of this studies will provide us new structural clues to develop more powerful DNMT1 inhibitors for colon cancer and leukemia therapy. Moreover, our work will lay the foundation for further development of innovative drugs with proprietary intellectual property rights. In the present study, we are anticipating to obtain 2-5 types of drug-like DNMT1 lead compounds. Meanwhile, more than 5 papers will be published on the SCI journals and 2 patents will be applied for the DNMT1 compounds.

DNA甲基转移酶（DNMTs）家族负责催化和维持DNA甲基化，其亚型DNMT1的表达异常与多种肿瘤的发生发展密切相关。因此，DNMT1成为一个热门的抗肿瘤新靶点。然而，现有DNMT1抑制剂体内半衰期短、毒副作用大、选择性不佳。本研究将基于已建立的抑制剂筛选与评价平台和已获新型DNMT1特异抑制剂，结合已建立的甲基化酶筛选平台，运用构效关系研究、靶向集中组合库等分子设计、结构优化和ADME/Tox预测等手段，加速设计并获得全新、类药性好的DNMT1特异性抑制剂。进一步，以发现的抑制剂为探针，围绕相关DNMT1靶标蛋白的结构与功能关系，设计、发现新型新先导化合物，在分子、细胞和动物水平进一步研究其作用机制，为靶向DNMT1，针对结肠癌等多种肿瘤的治疗提供新的药物先导结构，为开发具有自主知识产权的创新药物奠定基础。本研究将获得成药性高的先导化合物2～5个，发表SCI论文5篇以上，申请专利2项。

DNA甲基转移酶（DNMTs）家族负责催化和维持DNA甲基化，其亚型DNMT1的表达异常与多种肿瘤的发生发展密切相关。因此，DNMT1成为一个热门的抗肿瘤新靶点。然而，现有DNMT1抑制剂体内半衰期短、毒副作用大、选择性不佳。本研究将基于已建立的抑制剂筛选与评价平台，开展DNMT1药物发现与化学干预研究。首先，我们针对DNMT家族蛋白DNMT1和DNMT3A开展了动态调控机制的研究，发现了新的关键调控区域，为新型抑制剂的发现和设计提供了新的位点。其次，我们建立了稳定可靠的DNMT1特异性虚拟筛选评价模型和体外评价平台，并基于此筛选获得了两类选择性较好的DNMT1新型抑制剂，并针对其中一类DC_107系列化合物开展了优化改造工作，获得了目前活性、选择性最好的DNMT1小分子抑制剂，为该领域小分子化合物的发现研究提供技术平台和新的药物先导结构，为开发具有自主知识产权的创新药物奠定基础。通过项目全体成员的努力，各学科紧密合作，顺利完成了本课题的各项既定研究任务。共发表致谢本基金号的SCI论文 20 篇，申请专利 4 项,培养博士毕业生5名，硕士毕业生1名。

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