Synoviolin inhibitors for treatment of fibrosis

类风湿性关节炎（RA）显著影响生活质量。我们最近克隆了一种E3泛素连接酶，它与内质网相关的降解途径有关。滑膜因子在类风湿滑膜细胞中高度表达，并参与RA的发病。抑制滑膜活动是治疗类风湿性关节炎的一种潜在有效的治疗方法。我们最近发现了两类小分子，命名为LS-101和LS-102，它们抑制滑膜小提琴活动。LS-102选择性地抑制滑膜酶活性，而LS-101抑制广泛的ring型E3连接酶。此外，这些抑制剂抑制类风湿滑膜细胞的增殖，并显着降低RA和肝纤维化小鼠模型的疾病严重程度。我们的研究结果表明，抑制滑膜鞘是治疗纤维化的一种潜在的有用方法。

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, an E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation pathway. Synoviolin is highly expressed in rheumatoid synovial cells and is involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We recently identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA and liver fibrosis. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of fibrosis.