UBC12-DCN1靶向小分子抑制剂的设计、合成及其在胃癌中对NEDDylation的调控机制研究

NEDDylation is a new kind of ubiquitination, and may impact on the proteasome mediated protein degradation by E1 activation, E2 conjunction and E3 ligation. UBC12 and DCN1 are two key E2 and E3, respectively, and may form a complex and contribute to NEDDylation in the progress and development of gastric cancer. When the UBC12-DCN1 complex is inactivated by unspecific NEDDylation inhibitor or deformed by RNAi, cell proliferation and migration can be abrogated. Hence, UBC12-DCN1 is considered as a valuable anti-cancer target and UBC12-DCN1 inhibitor can be applied to study the biological role of NEDDylation in gastric cancer. Herein, we plan to design, synthesis a series of amino acid derivates based on our high throughput virtual screening result in order to have some specific and potent UBC12-DCN1 inhibitors with the aid of CAAD and SAR. Further in vitro and in vivo biological activity and mechanism study will also be performed to support the discovery of UBC12-DCN1 inhibitor.

NEDDylation是一类新型类泛素化翻译后修饰，通过E1激活、E2偶联、E3连接级联反应控制细胞内蛋白酶体降解途径。其中，E2偶联酶UBC12及E3连接酶DCN1通过级联反应形成蛋白复合物，发挥NEDDylation活性，调节胃癌的发生发展。用广谱性小分子NEDDylation抑制剂或RNAi阻断UBC12-DCN1蛋白复合物的形成可抑制细胞生长、转移和侵袭。因此研究UBC12-DCN1抑制剂对进一步探索NEDDylation生物学意义和抗肿瘤药物研发具有重要的科学研究价值。本项目计划在前期高通量虚拟筛选基础上设计、合成一系列氨基酸类小分子UBC12-DCN1抑制剂。通过计算机辅助药物设计和构效关系分析，优化获得结构新颖、高效的UBC12-DCN1抑制剂，研究其对NEDDylation作用机制；同时在细胞及动物水平研究小分子UBC12-DCN1抑制剂的作用机制和抗肿瘤活性。

NEDDylation是一类新型类泛素化翻译后修饰，通过E1激活、E2偶联、E3连接级联反应控制细胞内蛋白酶体降解途径。其中，E2偶联酶UBC12及E3连接酶DCN1通过级联反应形成蛋白复合物，发挥NEDDylation活性，调节胃癌的发生发展。用广谱性小分子NEDDylation抑制剂或RNAi阻断UBC12-DCN1蛋白复合物的形成可抑制细胞生长、转移和侵袭。因此研究UBC12-DCN1抑制剂对进一步探索NEDDylation生物学意义和抗肿瘤药物研发具有重要的科学研究价值。.本项目开发了药物及天然产物优势骨架结构的合成新方法，高效构建了包括联芳基、非天然氨基酸、二肽、吲哚及类天然产物等在内的多样性小分子化合物库，通过基于化合物库的高通量筛选、结构优化及活性机制评价等工作，发现了具有进一步临床开发价值的[1,2,4]三氮唑[1,5-a]嘧啶类、5-氰基-6-苯基嘧啶类、苯连1,2,4-三唑类和含苯基噻唑硫醇类的DCN1-UBC12抑制剂。