坏死性下垂
结肠炎
磷酸化
激酶
炎症性肠病
裂谷1
癌症研究
药理学
程序性细胞死亡
化学
生物
医学
免疫学
细胞生物学
细胞凋亡
生物化学
内科学
疾病
作者
Chong Zhang,Yiqin Luo,Qiaoling He,Shuai Liu,Andong He,Jie Yan
出处
期刊:Clinical Science
[Portland Press]
日期:2019-04-01
卷期号:133 (8): 919-932
被引量:19
摘要
Abstract A dramatic increase in the incidence of inflammatory bowel disease (IBD) has been observed in the past two decades, mainly in developed countries and also in developing regions. Necroptosis has been found to play an important role in the pathogenesis of IBD, suggesting its inhibitors are promising in clinic. However, clinical drugs targeting necroptosis are seriously lacking. Through screening a clinical compound library that contains 611 inhibitors, a pan-RAF inhibitor LY3009120 was found to be promising as a necroptosis inhibitor. LY3009120 inhibited necroptosis in vitro, and its inhibition against necroptosis was independent of its well-known activity to inhibit RAF. Surprisingly, LY3009120 prevented phosphorylation of receptor interacting serine/threonine kinase 1 (RIPK1) and subsequently phosphorylation of receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL) which happened during necroptosis. In vivo, LY3009120 significantly alleviated dextran sulfate sodium (DSS)-induced colitis as indicated by prevention of body weight loss, colon shortening, and decreased mortality. Furthermore, LY3009120 inhibited necroptosis of intestinal epithelial cells (IECs) and prevented intestinal barrier function loss. Consistently, LY3009120 decreased DSS-induced colonic inflammation, as indicated by decreased infiltration of macrophages and neutrophils, and decreased colonic TNF-α, IL-6, and IL-1β level in DSS treated mice. These results indicate that an anti-cancer pan-RAF inhibitor LY3009120 is a necroptosis inhibitor and may serve as a potential therapeutic drug for colitis.
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