中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease

文献类型：期刊论文

作者Huang, Yuqing6,7; Ning, Yi3,4,5; Chen, Zhiwei2,3; Song, Peiran4,5,7; Tang, Haotian4,5,7; Shi, Wenhao7; Wan, Zhipeng7; Huang, Gege7; Liu, Qiupei1,4,5; Chen, Yun2
刊名MOLECULES
出版日期2024-04-01
卷号29期号:8页码:17
关键词IRAK4 inhibitor peritonitis inflammatory bowel disease (IBD) macrophage
DOI10.3390/molecules29081803
通讯作者Duan, Wenhu(whduan@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn)
英文摘要IRAK4 is a critical mediator in NF-kappa B-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-alpha and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-alpha and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.
WOS关键词NEUTROPHIL MIGRATION ; LIVER-INJURY ; MODELS ; MACROPHAGES ; COLITIS
资助项目National Natural Science Foundation of China
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001209912900001
出版者MDPI
源URL[http://119.78.100.183/handle/2S10ELR8/310974]  
专题新药研究国家重点实验室
通讯作者Duan, Wenhu; Xie, Hua
作者单位1.Univ Nottingham Ningbo China, Dept Chem & Environm Engn, Sci & Engn Bldg, Ningbo 315100, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Small Mol Drug Res Ctr, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
6.Guizhou Med Univ, Coll Pharm, Guiyang 561113, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Yuqing,Ning, Yi,Chen, Zhiwei,et al. A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease[J]. MOLECULES,2024,29(8):17.
APA Huang, Yuqing.,Ning, Yi.,Chen, Zhiwei.,Song, Peiran.,Tang, Haotian.,...&Xie, Hua.(2024).A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.MOLECULES,29(8),17.
MLA Huang, Yuqing,et al."A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease".MOLECULES 29.8(2024):17.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。