以Flavokawain A为先导的NEDDylation抑制剂的设计、合成及作用机制研究

NEDDylation is a process of protein post-transnational modification, which adds a tag to a protein for regulation of its function. Inhibition of NEDDylation has been shown to result in inhibition of cell proliferation and induction of apoptosis and autophagy. Therefor it became an important innovation of cancer chemotherapeutic to inhibit NEDDylation. However, the reported NEDDylation inhibitors at present is relatively lacking. Therefore, there are increasingly interesting in developing more novel NEDDylation inhibitors for treatment of cancer. We are the first to report in Oncotarget that natural product Flavokawain A (FKA) is a potent NEDDylation inhibitor. Besides, we synthesized a FKA derivative with a high activity of NEDDylation inhibition, this compound may target at Ubc12. Based on these works, we are going to design and synthesis FKA derivatives with computer-aided molecular design (CAMD) bringing in reported active fragments. Screen out potent compounds for NEDDylation and cancer cell growth inhibition. Study the functional mechanism using techniques like proteomic. And test the result in the experiments in vivo and in vitro. These studies will provide a theoretical foundation for NEDDylation inhibitors as new antitumor targeted molecules.

NEDDylation是一种蛋白质的翻译后修饰过程，该过程通过修饰底物结构影响底物功能。当该过程受到抑制，细胞的增殖能力会减弱，进而导致细胞凋亡或自噬。因此，抑制NEDDylation是肿瘤化疗的重要创新。然而现有的NEDDylation抑制剂种类较少。所以，研究新型NEDDylation抑制剂有着重大的意义。我们首次在Oncotarget报道了天然产物Flavokawain A（FKA）可以抑制NEDDylation。并合成了具有较强NEDDylation抑制活性的FKA类似物，其作用靶点可能是Ubc12。本项目拟在前期研究的基础上借助计算机辅助设计引入已知的活性片段，合成类似物。筛选具有较高肿瘤抑制活性及NEDDylation抑制活性的化合物。通过蛋白质组学等手段研究探究其作用机制，并在体内外实验中进行验证。为NEDDylation抑制剂作为抗肿瘤靶向分子提供理论依据。

NEDDylation是体内调控蛋白降解的重要机制，对于肿瘤的发展有重要的影响。影响NEDDylation进而抑制肿瘤是抗肿瘤药物化学的重要研究方向。本项目以化合物FKA为先导，并结合前期工作基础和相关文献报道，利用拼合原理、骨架跃迁、生物电子等排等手段设计、合成NEDDylation抑制剂15个系列共300余个。项目组选取3株以上NEDDylation高活化的肿瘤细胞对每一个系列的化合物进行了抗肿瘤活性筛选。对每个系列最优的化合物进行了抗肿瘤机制的研究。项目进行中我们报道了多个具有较高活性的NEDDylation抑制剂和抗肿瘤化合物。此外我们还首次报道了可作为抗肿瘤化合物的NEDDylation激动剂。通过项目的开展，我们共发表SCI学术论文15篇，申请国家发明专利5项，培养研究生6人。超额完成任务。