Details

Autor(en) / Beteiligte

• 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

Titel

JT002, a small molecule inhibitor of the NLRP3 inflammasome for the treatment of autoinflammatory disorders

Ist Teil von

• Scientific reports, 2023-08, Vol.13 (1), p.13524-13524, Article 13524

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2023

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.