학술논문
JT002, a small molecule inhibitor of the NLRP3 inflammasome for the treatment of autoinflammatory disorders
Document Type
Original Paper
Author
Ambrus-Aikelin, Geza; Takeda, Katsuyuki; Joetham, Anthony; Lazic, Milos; Povero, Davide; Santini, Angelina M.; Pranadinata, Rama; Johnson, Casey D.; McGeough, Matthew D.; Beasley, Federico C.; Stansfield, Ryan; McBride, Christopher; Trzoss, Lynnie; Hoffman, Hal M.; Feldstein, Ariel E.; Stafford, Jeffrey A.; Veal, James M.; Bain, Gretchen; Gelfand, Erwin W.
Source
Scientific Reports. 13(1)
Subject
Language
English
ISSN
2045-2322
Abstract
The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle–Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.