NLRP3-IN-87

NLRP3-IN-87 is a selective, orally active inhibitor of NLRP3 with a dissociation constant (Kd) of 0.23 μM. It binds directly to the NACHT domain of NLRP3, disrupting interactions with NLRP3-NEK7 and NLRP3-ASC, inhibits ASC oligomerization, and blocks inflammasome assembly. This compound suppresses caspase-1 activation and IL-1β secretion. NLRP3-IN-87 exhibits anti-inflammatory and analgesic properties, alleviating joint swelling, inflammation, and pain in an acute gout mouse model induced by MSU. NLRP3-IN-87 is applicable in research related to gout.

NLRP3:0.23 μM (Kd)

NLRP3-IN-87 (Compound M48) directly binds to the NACHT domain of purified human NLRP3 protein with a Kd of 0.23 μM. When pretreated for 30 minutes at concentrations between 1-20 nM, NLRP3-IN-87 effectively inhibits IL-1β secretion mediated by the NLRP3 inflammasome in BMDM cells, with an IC50 of 11.9 nM, and it also blocks the activation of caspase-1. At concentrations ranging from 50-500 nM, it dose-dependently disrupts the interaction between NLRP3 and NEK7 and ASC in LPS/Nigericin-activated mouse BMDMs. Furthermore, NLRP3-IN-87 at 10-100 nM for 30-minute pretreatment inhibits dose-dependent ASC oligomerization and speck formation in LPS/Nigericin-activated mouse bone marrow-derived macrophages (BMDMs). In LPS-stimulated mouse BMDM lysates, concentrations of 0.01-1000 μM over 10-90 minutes enhance the thermal stability of the NLRP3 protein in a concentration- and time-dependent manner. Additionally, at 0-400 μM over 24 hours, it exhibits low cytotoxicity in primary human hepatocytes.

NLRP3-IN-87 (Compound M48), administered orally at a dose of 3 mg/kg as a single dose 0.5 hours before MSU injection, significantly reduces foot swelling, mechanical pain, and IL-1β levels in an ICR mouse model of gout. Further evaluation with a dosage of 100-200 mg/kg per day for 14 days via gavage reveals no significant toxicity in ICR mice, assessed by body weight, organ weight, histopathology, and serum biomarkers.