MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel potential therapeutic for NLRP3 driven diseases

Abstract

NLRP3 is a critical component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes and complex diseases such as multiple sclerosis, type II diabetes and atherosclerosis. There is a compelling rationale to develop a potent, selective inhibitor of NLRP3. We demonstrate that a small molecule, MCC950, specifically blocks NLRP3 activation at nanomolar potency in response to numerous stimuli. MCC950 potently inhibits ASC oligomerisation, caspase-1 activation, IL-1β secretion and cell death in response to NLRP3 but not AIM2, NLRC4 or NLRP1 inflammasome activation. MCC950 can block IL-1b in vivo and attenuate..