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

Autor: Ambrus-Aikelin G; Jecure Therapeutics, San Diego, CA, USA., Takeda K; Department of Pediatrics, National Jewish Health, Denver, CO, USA., Joetham A; Department of Pediatrics, National Jewish Health, Denver, CO, USA., Lazic M; Jecure Therapeutics, San Diego, CA, USA., Povero D; Jecure Therapeutics, San Diego, CA, USA. povero.davide@mayo.edu.; Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA. povero.davide@mayo.edu., Santini AM; Jecure Therapeutics, San Diego, CA, USA., Pranadinata R; Jecure Therapeutics, San Diego, CA, USA., Johnson CD; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., McGeough MD; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Beasley FC; Jecure Therapeutics, San Diego, CA, USA., Stansfield R; Jecure Therapeutics, San Diego, CA, USA., McBride C; Jecure Therapeutics, San Diego, CA, USA., Trzoss L; Jecure Therapeutics, San Diego, CA, USA., Hoffman HM; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Feldstein AE; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Stafford JA; Jecure Therapeutics, San Diego, CA, USA., Veal JM; Jecure Therapeutics, San Diego, CA, USA., Bain G; Jecure Therapeutics, San Diego, CA, USA., Gelfand EW; Department of Pediatrics, National Jewish Health, Denver, CO, USA.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Aug 19; Vol. 13 (1), pp. 13524. Date of Electronic Publication: 2023 Aug 19.
DOI: 10.1038/s41598-023-39805-z
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje