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.

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.

• Authors: Aichun Li, Qin Yang, Guohua Lou, Yanning Liu, Hongguang Xia, Zhi Chen
• Journal: Life sciences (Life Sci) Vol. 273 Pg. 119304 (May 15 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 33662432 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• GTPase-Activating Proteins
• Indoles
• Lipopolysaccharides
• Protective Agents
• Ralbp1 protein, mouse
• Reactive Oxygen Species
• Galactosamine

Topics

• Animals
• GTPase-Activating Proteins (antagonists & inhibitors)
• Galactosamine (toxicity)
• Humans
• Indoles (chemistry)
• Lipopolysaccharides (toxicity)
• Liver Failure, Acute (chemically induced, drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Necroptosis
• Protective Agents (pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• U937 Cells