Study on chemical biology for protein SUMOylation

本研究的目的是利用化学生物学方法阐明蛋白质SUMOylation在癌变中的作用。使用基于原位细胞的SUMOylation检测系统，我们鉴定了几种SUMOylation的小分子抑制剂，包括spectomycin B1作为SUMO E2 （Ubc9）抑制剂。我们的研究结果表明，Ubc9抑制剂如spectomycin B1有潜力作为治疗erα依赖性乳腺癌的药物。此外，我们通过原位deSUMOylation实验鉴定了一种新的deSUMOylatuon酶，SENP1，抑制剂。我们发现SENP1抑制剂降低了hif -1 α的活性，hif -1 α是缺氧微环境下癌症生存的重要转录因子。此外，我们成功开发了一种新的检测系统，用于使用分裂荧光素酶互补检测SUMO和SIM之间的非共价相互作用，并鉴定了第一个抑制SUMO依赖蛋白-蛋白相互作用的小分子。

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.