Study on chemical biology for protein SUMOylation

本研究的目的是用化学生物学方法阐明蛋白SUMO化在肿瘤发生中的作用。使用基于细胞的原位SUMO化测定系统，我们鉴定了几种SUMO化的小分子抑制剂，包括作为SUMO E2（Ubc 9）抑制剂的壮观霉素B1。我们的研究结果表明，Ubc 9抑制剂，如壮观霉素B1，有可能作为治疗ER α依赖性乳腺癌的药物。此外，我们通过原位去SUMO化测定鉴定了一种新的去SUMO化酶SENP 1抑制剂。我们发现SENP 1抑制剂降低了HIF-1 α的活性，HIF-1 α是缺氧微环境下癌症存活的重要转录因子。此外，我们成功地开发了新的检测系统，用于检测SUMO和SIM之间的非共价相互作用，使用分裂荧光素酶互补，并确定了第一个小分子，抑制SUMO依赖的蛋白质-蛋白质相互作用。

The aim of this study is to elucidate roles of protein SUMOylation in carcinogenesis using a chemical biology approach. Using an in situ cell-based SUMOylation assay system, we identified several small molecule inhibitors of SUMOylation including spectomycin B1 as SUMO E2 (Ubc9) inhibitor. Our findings suggested that Ubc9 inhibitors such as spectomycin B1 have a potential as a therapeutic agent against ERalpha-dependent breast cancers. Furthermore, we identified a novel deSUMOylatuon enzyme, SENP1, inhibitor by an in situ deSUMOylation assay. We found that SENP1 inhibitor reduced the activity of HIF-1alpha,an important transcriptional factor for cancer survival under hypoxia microenvironment. In addition, we succeeded in developing novel assay systems for detecting non-covalent interactions between SUMO and SIM using a split-luciferase complementation and identified first small molecules that inhibit SUMO-dependent protein-protein interactions.