2034-LB: Drug Screening Identifies Dicoumarol as a Novel IRE1α Inhibitor That Protects Mice from ER Stress-Induced Liver Damage

Excessive nutrition intake leads to endoplasmic reticulum (ER) stress and activate unfolded protein response (UPR) in the liver. Depending on the level and duration of ER stress, IRE1α, the most conserved branch of UPR, a dual-functional ER transmembrane protein promotes either adaptation or apoptosis. Transient activation of IRE1α induces trans auto-phosphorylation and binds an ATP to its kinase domain, subsequently driving homo-oligomerization and exposure of its RNase domain, which catalyzes an unconventional splicing of XBP1 mRNA and generates an adaptive transcription factor XBP1s to restore ER homeostasis. However, under excess and chronic ER stress, hyperactivation of IRE1α expands RNase substrate repertoire to many other mRNA species, known as regulated IRE1-dependent decay (RIDD), which leads to apoptosis. To modulate the activity and effects of IRE1α, we performed a virtual screening targeting the kinase domain of IRE1α which contains a natural pocket structure to identify ATP-competitive small molecules. To validate the effects of those small molecules, an IRE1α-XBP1s activity reporter cell line was employed to further discriminate the candidates that inhibit IRE1α activity using fluorescence-activated cell sorting. Based on these strategies, we identified dicoumarol as a novel IRE1α inhibitor, which inhibits ER stress agonist-induced activation of IRE1α both in vitro and in vivo. Particularly, dicoumarol ameliorates tunicamycin- and tetrachloromethane-induced acute hepatic ER stress consequently protecting the liver from damage. Thus, dicoumarol shows a powerful hepatic protective effect, however, the potency of dicoumarol in the application of chronic ER stress, such as obesity and type 2 diabetes, needs further determination.