Researchers described the preclinical profile of JT002, a novel and orally bioavailable small molecule inhibitor of the NLRP3 inflammasome.
By Pooja Toshniwal PahariaAug 24 2023Reviewed by Sophia Coveney In a recent study published in Scientific Reports, researchers described the preclinical profile of JT002, a novel and orally bioavailable small molecule inhibitor of the NLR family pyrin domain-containing 3 inflammasome.
The team investigated JT002 efficacy in vivo after oral dosing in a murine model of cryopyrin-associated periodic syndromes and two models of neutrophilic inflammation in the airways, in addition to the in vivo pharmacodynamic and pharmacokinetic profiles of the small molecule NLRP3 inhibitor. Male Sprague-Dawley rats and Beagle dogs were administered JT002 intravenously and orally for pharmacokinetic evaluation.
Intracellular caspase-1 activity in nigericin- and LPS-activated human peripheral blood mononuclear cells was evaluated. Next, the team investigated whether JT002 blocked ASC complex assembly by immunostaining and imaging analyses. Results JT002 selectively and potently inhibited pro-inflammatory cytokine generation and caspase 1-triggered pyroptosis using various stimuli.
JT002 was effective in acute as well as chronic models. The study findings indicated that NLRP3 activation was critical for ozone-induced inflammation in the airways and interleukin-17-induced neutrophilic asthma, underpinning that NLRP3 could be targeted with JT002 for therapeutic benefits in managing steroid-resistant and severe neutrophilic asthma.
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