发展新机制的创新抗肿瘤药物是实现肿瘤有效治疗的重要途径。蛋白酶体是已知的抗肿瘤靶点，抑制其水解活性亚基20SCP的药物已进入临床应用，但仍存在治疗面窄及易产生耐药等不足。其19SRP亚基催化的去泛素化过程是蛋白酶体降解蛋白的关键步骤，最新报道与我们前期结果发现，选择性阻断19SRP的去泛素化功能，可实现对肿瘤生存-死亡平衡相关的NF-KB/p53信号网络的整体调控，在体内外产生明确的抗肿瘤作用，是新的蛋白酶体抑制剂设计思路。本课题拟基于此一新生长点，结合已发现活性分子的结构特征与去泛素化酶的作用特点，提出设计新结构化合物库系列；通过活性筛选，发现选择性抑制19SRP去泛素化酶的高活性先导分子；并研究其抑制去泛素化酶的分子机制；同时探索19SRP去泛素化功能抑制引发凋亡通路应答的基本规律；在体内外评价其抗肿瘤活性，为新一代基于蛋白酶体19SRP去泛素化抑制新机制的抗肿瘤药物研发提供坚实基础。

Development of new mechanism based antitumor drugs is an important approach for efficient tumor treatment. Proteasome have proven to be antitumor drug target, several drugs based on its hydrolysis subunits (20SCP) inhibition have entered clinical application, but their clinical application were limited owing to the narrow therapeutic window and acquired drug resistance by cancer cells. 19SRP catalyzed deubiquitin is key event of proteasome dependent degradation of target proteins, the latest literature and our preliminary results revealed that selectively inhibit the deubiqutine activity of 19SRP, can regulate survival - death balance related NF-KB/p53 signaling network of tumor cells, and lead to efficient anti-tumor effects in vivo and in vitro.Inspired by our previous findings, this project will combine the structure active PAC-T type compounds found in our previous work, with the characteristics of ubiquitinase functions, design, evaluation and discovery of new selective 19SRP related ubiquitinase inhibitors; and investigate its molecular mechanism of deubiquitinase inhibition and apopotosis; evaluate its antitumor activity in vivo and in vitro. This work will afford important basis for discovery of new generation of anticancer drugs based on proteasome 19SRP deubiquitin inhibition.