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

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-08-20 DOI:10.1007/s11030-025-11316-1

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

{"title":"Discovery of 7-azaindole-3-acrylamide inhibitors of inflammasomes/IL-1β for the treatment of inflammatory bowel disease.","authors":"Yuyun Yan, Xiuxiu Zhang, Ruiwen Wu, Xiangting Liang, Yiming Luo, Jie Yang, Dan Wu, Geng Lin, Ping Sun, Zhongjin Yang, Wenhui Hu","doi":"10.1007/s11030-025-11316-1","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-025-11316-1","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

7-叠氮多尔-3-丙烯酰胺炎症小体抑制剂/IL-1β治疗炎症性肠病的发现

目前，很大一部分炎症性肠病（IBD）患者对免疫抑制剂和生物制剂等常规药物治疗无效。IL-1信号阻断对于这些无反应的IBD患者是一种很有希望的治疗策略。在这项研究中，我们鉴定了一种新的抗nlrp3 / IL-1β抑制剂，7-氮杂吲哚类似物Y19，其IC50值为1.26 μM。机制研究表明，它通过破坏关键蛋白相互作用来抑制NLRP3炎症小体的组装和激活，包括NEK7-NLRP3、NLRP3-NLRP3、NLRP3- asc和ASC-ASC。此外，它还抑制AIM2和NLRC4炎症小体途径。在小鼠结肠炎模型中，Y19作为一种泛炎性体抑制剂，显示出与托法替尼相当的抗炎功效，托法替尼是一种Janus激酶抑制剂，通常用于常规治疗难治性IBD患者。这一发现强调了炎症小体/ IL-1β抑制剂作为治疗IBD的一种有希望的策略的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;