mcc-950 and Disease-Models--Animal

Acute respiratory distress syndrome/chronic obstructive pulmonary disease (ARDS/COPD) is a diffuse inflammatory injury of the lung that is characterized by respiratory distress and vascular leakage and is caused by various factors. Although the treatment strategy for ARDS/COPD continues to be improved, it still lacks effective drugs. MCC950 is a potent and selective inhibitor ofthe nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome. However, there have been no reports on the effects of MCC950 on lipopolysaccharide (LPS)-induced lung inflammation in mice. The objective of the present study was to evaluate the effects of MCC950 (given either intranasally or intraperitoneally) on inhibiting LPS-induced lung inflammation in mice. Acute lung inflammation was induced by intratracheal administration of LPS in ICR mice. The results showed that MCC950 at 50 mg/kg efficiently suppressed neutrophil lymphocytes (p < 0.001) and macrophage accumulation (p < 0.01) in bronchoalveolar lavage fluid (BALF) in LPS-instilled mice. In addition, hematoxylin and eosin (H&E) staining revealed that MCC950 at 50 mg/kg significantly inhibited pathological progress in the lung tissues (p < 0.01). Furthermore, treatment with MCC950 substantially reduced mRNA expression of IL-1β, IL-8, TGF-β1, and MMP-9 and also reduced protein levels of IL-1β, IL-18 and caspase-1 at 24 h after LPS instillation. The results of the present study indicate that MCC950 effectively inhibits LPS-induced lung inflammation in vivo, which can be considered for clinical translation.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Furans; Indenes; Lipopolysaccharides; Mice; Mice, Inbred ICR; Molecular Structure; Neutrophil Infiltration; NLR Family, Pyrin Domain-Containing 3 Protein; Pneumonia; Structure-Activity Relationship; Sulfonamides

NLRP3 inflammasome activation plays a critical role in inflammation and its related disorders. Herein we report a hit-to-lead effort resulting in the discovery of a novel and potent class of NLRP3 inflammasome inhibitors. Among these, the most potent lead 40 exhibited improved inhibitory potency and almost no toxicity. Further mechanistic study indicated that compound 40 inhibited the NLRP3 inflammasome activation via suppressing ROS production. More importantly, treatment with 40 showed remarkable therapeutic effects on LPS-induced sepsis and DSS-induced colitis. This study encourages further development of more potent inhibitors based on this chemical scaffold and provides a chemical tool to identify its cellular binding target.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Chalcones; Colitis; Disease Models, Animal; Drug Design; Female; Inflammasomes; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Reactive Oxygen Species; Sepsis; Structure-Activity Relationship

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

Topics: Animals; Carrier Proteins; Cryopyrin-Associated Periodic Syndromes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Indenes; Inflammasomes; Inflammation; Interleukin-1beta; Mice; Multiple Sclerosis; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfonamides; Sulfones