Discovery of 7-azaindole-3-acrylamide inhibitors of inflammasomes/IL-1β for the treatment of inflammatory bowel disease.

Currently, a significant proportion of patients with inflammatory bowel disease (IBD) fail to respond to conventional drug therapies such as immunosuppressants and biologic agents. IL-1 signaling blockade is a promising therapeutic strategy for these unresponsive IBD patients. In this study, we identified a novel anti-NLRP3/ IL-1β inhibitor, the 7-azaindole analogue Y19, which exhibits an IC₅₀ value of 1.26 μM. Mechanistic investigations revealed that it suppresses NLRP3 inflammasome assembly and activation by disrupting critical protein-protein interactions, including NEK7-NLRP3, NLRP3-NLRP3, NLRP3-ASC, and ASC-ASC. Additionally, it also inhibits the AIM2 and NLRC4 inflammasome pathways. In a murine model of colitis, Y19, as a pan-inflammasome inhibitor, demonstrates anti-inflammatory efficacy comparable to that of tofacitinib, a Janus kinase inhibitor commonly prescribed for IBD patients refractory to conventional therapies. This finding highlights the potential of inflammasomes/ IL-1β inhibitors as a promising strategy for the treatment of IBD.