蛋白质的动态修饰是细胞乃至机体适应内外界刺激的重要途径，可作为分子靶向药物筛选的关键节点。前期研究表明，核受体Nur77及其靶向小分子化合物在血糖调控、细胞自噬性死亡诱导及脓毒症抑制等过程中发挥重要作用。乳腺癌的发生发展与脂肪酸代谢密切相关。预实验结果表明，Nur77可通过调控脂肪酸代谢抑制乳腺癌进程，然而随着乳腺癌的发展Nur77发生磷酸化修饰进而导致其泛素化降解。在此，我们将探究Nur77对脂代谢的调控机制,分析上游因子影响Nur77修饰的功能作用；确定调控Nur77动态修饰的关键节点，构建筛选模型，从自有的化合物库中筛选靶向Nur77抑制乳腺癌的小分子化合物；进一步开展构效关系研究，改造优化化合物，进行体内药效评价，以期获得活性优异的先导化合物。本申请符合指南的3.3条：“从分子、细胞、组织和个体等多个层次开展对生物大分子动态修饰识别及功能发挥的化学干预研究，发现相应的先导化合物”。

Dynamic modification of proteins is important for cells and organisms in adaptation to external or internal stimuli, and thus is considered as a key node in targeting drugs screening. Our previous studies have shown that nuclear receptor Nur77 and its targeting compounds play important roles in the regulation of blood glucose, induction of autophagic cell death and inhibition of sepsis-associated inflammation. It has been accepted that the occurrence and development of breast cancer is closely related to the metabolism of fatty acids. Our preliminary experiments strongly suggested the inhibitory effect of Nur77 on the development of breast cancer through the regulation of fatty acid metabolism. With the progression of breast cancer, Nur77 is phosphorylated, leading to its ubiquitination and degradation. In this project, we will explore the mechanism of Nur77 in regulating fatty acid metabolism and understand how Nur77 functions are controlled by its upstream factors through regulating the dynamic modifications of Nur77. After confirmation of key nodes in Nur77 dynamic modification, a suitable screening model will be set up to screen small molecule compounds that specifically target Nur77 to inhibit the progression of breast cancer in our unique compound library. Furthermore, we will study the structure-activity relationship (SAR) to further modify and optimize the compounds, and finally evaluate their pharmacokinetics in vivo to obtain the leading compounds with excellent activity. In sum, this project is matched well with the Article 3.3 of the application guideline: "perform the chemical intervention study between the dynamic modifications and biological functions of macromolecules at the molecular, cellular, tissue and individual levels, so as to find the corresponding lead compounds".