Ph+慢性粒细胞白血病中原癌蛋白SET的Neddylation修饰与化学干预

随着伊马替尼等酪氨酸激酶抑制剂（TKI）的广泛使用，临床耐药情况变得日趋严重，已成为治疗费城染色体阳性慢性粒细胞白血病（Ph+-CML）的重大挑战。本课题组前期发现，苯氧基嘧啶化合物TGI1002可特异性结合原癌蛋白SET，通过干扰SET与PP2A相互作用有效对抗T315I突变导致的耐药Ph+-CML。近期又发现SET存在Neddylation修饰并参与它与其它蛋白质间的相互作用。.本课题将系统分析SET的Neddylation修饰位点和相关修饰酶，研究Neddylation修饰后SET蛋白参与的信号转导网络及其调控，验证SET Neddylation修饰与Ph+-CML及其耐药发生发展的相关性，同时设计和合成干预SET Neddylation修饰的小分子化合物并在分子、细胞及动物水平验证其有效性，为解决TKI耐药问题和治疗Ph+-CML提供新的靶标和原创分子。

Along with the wide use of the Tyrosine kinase inhibitor (TKI), such as, Imatinib, drug resistance has become a major issue in clinical applications and also a big challenge for the therapy of Philadelphia chromosome-positive chronic myelocytic leukemia (Ph+-CML). We previously found a novel 2-pheyloxypyrimidine compound TGI1002 that can effectively inhibit the proliferation of Ph+-CML cells with BCR-ABL T315I mutation. By binding to oncoprotein SET, TGI1002 can specifically disrupt SET-PP2A interaction. Recently, we identified for the first time that SET has NEDD8 conjugation and its neddylation participates in its interactions with other proteins. In the present study, we will elucidate the E3 ligase for SET neddylation and the key amino acids of SET involved in this process, investigate the regulation and biological consequences of SET neddylation, and validate the correlation between SET neddylation and the development of Ph+-CML. Meanwhile, we will also design and synthesize small molecule SET neddylation inhibitors, and examine their efficacy at the molecular, cellular and animal levels, which will provide a new strategy and effective tools to fight TKI-resistant Ph+-CML.