Abstract
Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release of the proinflammatory cytokines interleukin (IL)-1β and IL-18 and induces pyroptosis (lytic cell death). These events drive chronic inflammation, and as such, NLRP3 has been implicated in a large number of human diseases. These range from autoimmune conditions, the simplest of which is NLRP3 gain-of-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, to large disease burden indications, such as atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, and arthritis. The potential clinical utility of NLRP3 inhibitors is substantiated by an expanding list of indications in which NLRP3 activation has been shown to play a detrimental role. Studies of pharmacological inhibition of NLRP3 in nonclinical models of disease using MCC950 in combination with human genetics, epigenetics, and analyses of the efficacy of biologic inhibitors of IL-1β, such as anakinra and canakinumab, can help to prioritize clinical trials of NLRP3-directed therapeutics. Although MCC950 shows excellent (nanomolar) potency and high target selectivity, its pharmacokinetic and toxicokinetic properties limited its therapeutic development in the clinic. Several improved, next-generation inhibitors are now in clinical trials. Hence the body of research in a plethora of conditions reviewed herein may inform analysis of the potential translational value of NLRP3 inhibition in diseases with significant unmet medical need. SIGNIFICANCE STATEMENT: The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is one of the most widely studied and best validated biological targets in innate immunity. Activation of NLRP3 can be inhibited with MCC950, resulting in efficacy in more than 100 nonclinical models of inflammatory diseases. As several next-generation NLRP3 inhibitors are entering proof-of-concept clinical trials in 2020, a review of the pharmacology of MCC950 is timely and significant.
Highlights
Families of highly conserved pattern recognition receptors have evolved to occupy cellular membranes and cytosolic compartments of certain immune cells, such as macrophages and dendritic cells
Abstract——Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release of the proinflammatory cytokines interleukin (IL)-1b and IL-18 and induces pyroptosis. These events drive chronic inflammation, and as such, NLRP3 has been implicated in a large number of human diseases. These range from autoimmune conditions, the simplest of which is NLRP3 gainof-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, to large disease burden indications, such as atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, and arthritis
Unlike other inflammasomes, which are generally activated by discrete products of microbial origin, NLRP3 can be activated by many highly diverse stimuli, collectively termed pathogen-associated molecular patterns and ABBREVIATIONS: Amyloid b (Ab), amyloid b; AD, Alzheimer disease; AIM2, absent in melanoma 2; Agerelated macular degeneration (AMD), age-related macular degeneration; Ang II, angiotensin II; APP, amyloid precursor protein; ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; AT, a toxin; BAL, bronchoalveolar lavage; BDL, bile duct ligation; CANTOS-2, Canakinumab
Summary
Families of highly conserved pattern recognition receptors have evolved to occupy cellular membranes and cytosolic compartments of certain immune cells, such as macrophages and dendritic cells. A subset of intracellular receptors denoted Nod-like receptors (NLRs) assemble and oligomerize to form multiprotein intracellular complexes, which activate the caspase-1 cascade and lead to the production of proinflammatory cytokines IL-1b and IL-18. This multimolecular complex is called the “inflammasome.”. Unlike other inflammasomes, which are generally activated by discrete products of microbial origin, NLRP3 can be activated by many highly diverse stimuli, collectively termed pathogen-associated molecular patterns and ABBREVIATIONS: Ab, amyloid b; AD, Alzheimer disease; AIM2, absent in melanoma 2; AMD, age-related macular degeneration; Ang II, angiotensin II; APP, amyloid precursor protein; ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; AT, a toxin; BAL, bronchoalveolar lavage; BDL, bile duct ligation; CANTOS-2, Canakinumab. This review covers studies conducted between 2015 and 2020 with MCC950 and, in part, addresses some key questions regarding the potential translation of this molecule and other small-molecule NLRP3 inhibitors to the clinic
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