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

  • Sci Rep. 2023 Aug 19;13(1):13524. doi: 10.1038/s41598-023-39805-z.
Geza Ambrus-Aikelin  1 ,  Katsuyuki Takeda  2 ,  Anthony Joetham  2 ,  Milos Lazic  1 ,  Davide Povero  3  4 ,  Angelina M Santini  1 ,  Rama Pranadinata  1 ,  Casey D Johnson  5 ,  Matthew D McGeough  5 ,  Federico C Beasley  1 ,  Ryan Stansfield  1 ,  Christopher McBride  1 ,  Lynnie Trzoss  1 ,  Hal M Hoffman  5 ,  Ariel E Feldstein  5 ,  Jeffrey A Stafford  1 ,  James M Veal  1 ,  Gretchen Bain  1 ,  Erwin W Gelfand  2
Affiliations
  • 1. Jecure Therapeutics, San Diego, CA, USA.
  • 2. Department of Pediatrics, National Jewish Health, Denver, CO, USA.
  • 3. Jecure Therapeutics, San Diego, CA, USA. [email protected].
  • 4. Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA. [email protected].
  • 5. Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
PMID: 37598239 DOI: 10.1038/s41598-023-39805-z
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.

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