泛素化过程中可以调控细胞内几乎所有的生命过程。该过程由E1酶、E2酶、E3酶、蛋白酶体等蛋白家族催化的级联酶促反应所完成。去泛素化酶可以逆转泛素化过程，其成员USP7与癌症密切相关，是抗癌药物开发靶标。本项目计划首先希望能开发出新型的稳定USP7和泛素相互作用的选择性抑制剂。其次，本项目着眼于新型抑制剂小分子的工作机制，包括利用结构生物学和细胞生物学手段验证抑制剂稳定蛋白-蛋白相互作用（PPI）的工作方式。再次，我们计划利用新颖的USP7抑制剂探索去泛素化酶USP7在鼻咽癌发生发展中扮演的作用。通过本项目的科学研究，我们希望靶向USP7开发能够稳定PPI且具有优良的抗癌活性和选择性的小分子抑制剂，并把这个新型抑制剂开发的新策略推广到去泛素化酶家族中的其他成员上去。我们的研究成果将有助于对细胞内泛素化过程的化学干预并促进药物开发。

Ubiquitination regulates nearly all cellular processes. This post-translational.modification is typically achieved by an enzymatic cascade which is catalyzed by.E1, E2, E3 enzymes and proteasome. Deubiquitinating enzymes (DUB) can reverse ubiquitination. DUB protein USP7 has been reported to be a promising anticancer drug discovery target. First，we plan to discover selective and potent USP7 small molecule inhibitors which stabilize the interactions between USP7 and ubiquitin (Ub); Second, we plan to investigate the working mechanism of the novel inhibitor using structural biology and cell biology approaches to confirm its stabilizing PPI mechanism in vitro and in cell. Third, we will use novel USP7 inhibitors to study the roles of USP7 in the initiation and progression of Nasopharyngeal Carcinoma. In summary, we will discover PPI stabilizing USP7 inhibitors and apply this novel drug discovery strategy to other DUB members. Our results can be used to study complicated ubiquitination processes and promote drug discovery in the ubiquitin-proteasome system.