靶向USP28催化结构域的新型抗肿瘤抑制剂发现及其效应机制研究

USP28是去泛素化水解酶家族中最新的潜在抗肿瘤靶标分子之一，它在多个肿瘤相关的信号通路中发挥重要调控作用。特别是，USP28对结直肠癌的发生和发展具有较为明确的促进作用。然而，迄今为止，靶向USP28的抗肿瘤活性抑制剂发现工作尚仅见两篇文献报道，其作为抗肿瘤药物研发靶标的可靠性需要进一步的实验验证。在本项目工作中，我们拟通过实验筛选和基于结构的药物化学改造获得靶向USP28催化结构域的新型抗肿瘤抑制剂（变构抑制剂），并在解析抑制剂作用机制的同时兼顾探索USP28催化结构域“coiled-coil”插入单元的动态结构特征。项目的研究成果将为“coiled-coil”插入单元在USP28去泛素化功能执行过程中所发挥作用的解析提供新的数据信息，为明确USP28作为抗肿瘤药物研发靶标的可靠性提供参考数据，同时为开发靶向USP28的抗肿瘤候选药物提供新型的先导化合物（变构抑制剂）。

Ubiquitin-specific protease 28 (USP28) is one of the newest potential anti-cancer drug targets of deubiquitinase family, and has been found to be involved in multiple cancer-related signal pathways. Specially, evidences show that USP28 controls intestinal homeostasis and promotes colorectal cancer. However, up to date, there are only two literatures focusing on USP28 inhibitor development have been reported, and the robustness for USP28 as a target for anti-cancer drug development needs to be further verified. Here in this project, we will develop novel type of anti-cancer inhibitors (allosteric inhibitors) with USP28 catalytic domain as the target by a combination use of experimental screening and structure-guided active compound optimization. Then, in the following studies we will elucidate the working mechanisms of these inhibitors and explore the dynamic structural features of the inserted coiled-coil motif of USP28 catalytic domain by using the inhibitors as probes. The findings through conducting this project will provide important information for unravelling the potential role of the coiled-coil motif in the functional display of USP28, and for assessing the robustness of USP28 as a target for anti-cancer drug development. Moreover, novel type of anti-cancer drug leads (allosteric inhibitors) targeting USP28 will also be obtained.