2. Academic Validation
  3. 5-((7-Chloro-6-fluoro-1h-indol-3-yl) methyl)-3-methylimidazolidine-2,4-dione as a RIP1 inhibitor protects LPS/D-galactosamine-induced liver failure

5-((7-Chloro-6-fluoro-1h-indol-3-yl) methyl)-3-methylimidazolidine-2,4-dione as a RIP1 inhibitor protects LPS/D-galactosamine-induced liver failure

  • Life Sci. 2021 May 15;273:119304. doi: 10.1016/j.lfs.2021.119304.
Aichun Li 1,  Qin Yang 2,  Guohua Lou 3,  Yanning Liu 4,  Hongguang Xia 5,  Zhi Chen 6
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital College of Medicine, Zhejiang University, China. Electronic address: Liaichun@zju.edu.cn.
  • 2 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital College of Medicine, Zhejiang University, China. Electronic address: 3120102766@zju.edu.cn.
  • 3 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital College of Medicine, Zhejiang University, China. Electronic address: louguohua@zju.edu.cn.
  • 4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital College of Medicine, Zhejiang University, China. Electronic address: liuyanning@zju.edu.cn.
  • 5 Department of Biochemistry & Research Center of Clinical Pharmacy of the First Affiliated Hospital, Zhejiang University, China. Electronic address: hongguangxia@zju.edu.cn.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital College of Medicine, Zhejiang University, China. Electronic address: zjuchenzhi@zju.edu.cn.
PMID: 33662432 DOI: 10.1016/j.lfs.2021.119304
Abstract

Aims: Necroptosis, an inflammatory form of regulated necrosis mediated by receptor-interacting kinase 1 (RIP1), RIP3, and pseudokinase Mixed Lineage Kinase domain-like protein (MLKL) is extensively implicated in liver inflammatory disease. Thus identification small-molecule inhibitor of Necroptosis has emerged as a potential therapeutic strategy to prevent liver damage. In this study, we identified 5-((7-chloro-6-fluoro-1 h-indol-3-yl) methyl)-3-methylimidazolidine-2,4-dione (F-nec) as a novel potent Necroptosis Inhibitor.

Main methods: To find out the potent chemical inhibitors of Necroptosis, human monocytic U937 cells were treated with a combination of tumor necrosis factor alpha (TNFα) and a pan-caspase inhibitor z-VAD-fmk. LPS and D-galactosamine (LPS/GalN) were further employed to simulate acute liver failure to explore therapeutic potency of F-nec in vivo. In addition, a specific inhibitor of c-Jun NH (2)-terminal kinases (JNK) SP600125 and its activator anisomycin are used to elucidate its mechanisms in acute liver failure therapy. Necroptosis pathway related proteins were tested by western blot.

Key findings: In this study, we identified F-nec as a novel potent RIP1 inhibitor which efficiently blocked TNFα-induced Necroptosis in human and mice cells. Furthermore, pre-treatment of F-nec could prevent hepatic necrosis by reducing RIP1-mediated Necroptosis also effectively ameliorated LPS/GalN induced acute liver failure by attenuating cell death signaling-stimulated JNK pathway activation and then suppressing JNK-triggered inflammation.

Significance: Altogether, this study demonstrates that F-nec is a potent inhibitor of RIP1 and highlights its great potential for use in the treatment of RIP1-driven inflammatory liver diseases.

Keywords

Acute liver failure; Inflammation; JNK pathway; Necroptosis; RIP1 inhibitor.

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