2. Academic Validation
  3. A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease

A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease

  • Molecules. 2024 Apr 16;29(8):1803. doi: 10.3390/molecules29081803.
Yuqing Huang 1 2,  Yi Ning 3 4,  Zhiwei Chen 4 5,  Peiran Song 1 3,  Haotian Tang 1 3,  Wenhao Shi 1,  Zhipeng Wan 1,  Gege Huang 1,  Qiupei Liu 3 6,  Yun Chen 5,  Yu Zhou 1,  Yuantong Li 1,  Zhengsheng Zhan 5,  Jian Ding 3,  Wenhu Duan 4 5,  Hua Xie 1 2 3 4
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 2 College of Pharmacy, Guizhou Medical University, Guiyang 561113, China.
  • 3 Division of Antitumor Pharmacology & State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 Department of Chemical and Environment Engineering, Science and Engineering Building, The University of Nottingham Ningbo China, Ningbo 315100, China.
PMID: 38675622 DOI: 10.3390/molecules29081803
Abstract

IRAK4 is a critical mediator in NF-κB-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-α 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-α 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.

Keywords

IRAK4 inhibitor; inflammatory bowel disease (IBD); macrophage; peritonitis.

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