泛素偶联酶（E2）是泛素修饰系统中的重要成员，能够实现对细胞的代谢、分化、增殖等过程的精确调控。E2家族成员UBE2C作为细胞周期泛素连接酶（E3）APC/C的专属起始E2，能够直接调控APC/C的活性，广泛参与细胞周期进行的多个过程。已有研究表明，UBE2C与癌症的发生发展密切相关，有潜力成为新的药物靶标。由于E2独特的蛋白结构特点，目前全世界尚无一例针对E2的抗癌药物在临床研究上的报道。然而，基于片段的药物开发方法（FBDD）的出现让我们看到突破的可能性。该技术克服传统药物开发的缺点，能够在更加严苛的条件下获得小分子药物先导化合物。本项目将利用FBDD，结合X-ray以及NMR等生物物理学手段，开发出First-in-class水平的UBE2C小分子化合物抑制剂。

Ubiquitin coupling enzymes (E2s) are important members of the ubiquitin-proteasome system (USP). E2s realize the precise control of the life process, such as cells metabolism, cell differentiation and cell proliferation. UBE2C, an E2 enzyme, act as the initiation E2 of the anaphase-promoting complex/ cyclosome (APC/C) bearing ubiquitin ligase (E3) activity. UBE2C is required for destruction of mitotic cyclins, thereby assisting in the regulation of cell cycle progression through M phase. UBE2C also participates in mitotic spindle checkpoint control and catalyzing the dissociation of mitotic spindle checkpoint components from the APC/C. In the past decade, mounting evidences have shown that UBE2C is high expressed in a wide variety of human malignancies during tumorigenesis and tumor progression, which suggested that UBE2C is a potential anti-cancer target. So far, no inhibitor of E2 enzymes have been reported in clinical study because of the unique protein structure characteristic of E2 enzymes. Fragment based drug discover (FBDD) is a method that overcome the limitations of traditional drug development by acquiring small molecules lead compounds under severe condition. It can allow us to make a breakthrough for E2 enzymes inhibitor development. We will develop the small molecular inhibitor of UBE2C by using FBDD, combining with the biophysics experiment methods, such as NMR and X-ray. In addition, we will confirm the anti-cancer activity of the small molecular inhibitor by a series of in-vitro and in-vivo experiments.