A pan-RAF inhibitor LY3009120 inhibits necroptosis by preventing phosphorylation of RIPK1 and alleviates dextran sulfate sodium (DSS)-induced colitis

A dramatic increase in the incidence of inflammatory bowel disease (IBD) has been observed in the past 2 decades, mainly in developed countries but also in developing regions. Necroptosis has been found to play an important role in the pathogenesis of inflammatory bowel disease (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 RIPK1 and subsequently phosphorylation of RIPK3 and MLKL which happened during necroptosis. In vivo , LY3009120 significantly alleviated DSS-induced colitis as indicated by prevention of body weight loss, colon shortening and decreased mortality. Furthermore, LY3009120 inhibited necroptosis of intestinal epithelial cells 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 fo...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research