mcc-950 and Colitis

The NLRP3 inflammasome is a critical component of innate immunity, which defends internal and external threats. However, inappropriate activation of the NLRP3 inflammasome induces various human diseases. In this study, we discovered and synthesized a series of tetrahydroquinoline inhibitors of NLRP3 inflammasome. Among these analogues, compound

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cell Survival; Colitis; Dextran Sulfate; Drug Design; Female; Humans; Inhibitory Concentration 50; Interleukin-1beta; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Monocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Quinolines; Reactive Oxygen Species; Structure-Activity Relationship

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