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<p>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 <b>Y19</b>, which exhibits an IC<sub>50</sub> value of 1.26&#xa0;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, <b>Y19</b>, 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月20日

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  • Yuyun Yan,
  • Xiuxiu Zhang,
  • Ruiwen Wu,
  • Xiangting Liang,
  • Yiming Luo,
  • Jie Yang,
  • Dan Wu,
  • Geng Lin,
  • Ping Sun,
  • Zhongjin Yang,
  • Wenhui Hu

摘要

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.