ADS032 (ADS-032) is the first, reversible and stable dual NLRP1 and NLRP3 inflammasome inhibitor, inhibits nigericin‐induced NLRP3‐induced IL‐1β secretion from LPS‐primed iBMDMs with IC50 of 30 uM.
ADS032 inhibits ionophore‐ (nigericin) and crystalline‐ (silica) induced IL‐1β and LDH secretion from LPS‐primed iBMDMs, respectively, with no effect on LPS‐induced TNF‐α production.
ADS032 dose dependently inhibits IL‐1β secretion induced by the NLRP1 agonist L18‐MDP, but MCC950 has no effect.
ADS032 reduces L18‐MDP‐induced IL‐1β secretion in both WT and NLRP3‐deficient macrophages in a dose‐dependent manner.
ADS032 directly interacts proximal to the Walker B motif within the NACHT domain of both NLRP1 and NLRP3, thus inhibiting inflammasome activation and formation of each inflammasome complex.
ADS032 (20-350 uM) dose dependently reduces NLPR3‐induced ASC oligomerisation.
ADS032 effectively inhibits NLRP1 and NLRP3 inflammasome activity in human macrophages and bronchial epithelial cells.
ADS032 (200 mg /kg, methylcellulose, i.p.) inhibits NLRP3 in vivo and reduces acute silicosis‐associated pulmonary inflammation in vivo.