Abstract
Overexpression of tumor necrosis factor α (TNFα) is a hallmark of many inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and septic shock and hepatitis, making it a potential therapeutic target for clinical interventions. To explore chemical inhibitors against TNFα activity, we applied computer-aided drug design combined with in vitro and cell-based assays and identified a lead chemical compound, (E)-4-(2-(4-chloro-3-nitrophenyl) (named as C87 thereafter), which directly binds to TNFα, potently inhibits TNFα-induced cytotoxicity (IC50 = 8.73 μM) and effectively blocks TNFα-triggered signaling activities. Furthermore, by using a murine acute hepatitis model, we showed that C87 attenuates TNFα-induced inflammation, thereby markedly reducing injuries to the liver and improving animal survival. Thus, our results lead to a novel and highly specific small-molecule TNFα inhibitor, which can be potentially used to treat TNFα-mediated inflammatory diseases.
Keywords:
Cell Death; Cell Signaling; Computer Modeling; Inflammation; Small Molecules; Surface Plasmon Resonance (SPR); Tumor Necrosis Factor (TNF).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Caspases / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Disease Models, Animal
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Dose-Response Relationship, Drug
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HL-60 Cells
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Hepatitis, Animal / genetics
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Hepatitis, Animal / metabolism
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Hepatitis, Animal / prevention & control*
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Humans
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Hydrazones / chemistry
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Hydrazones / pharmacology
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation / prevention & control*
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Jurkat Cells
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K562 Cells
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MAP Kinase Kinase 4 / metabolism
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Mice
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Mice, Inbred BALB C
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Molecular Structure
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Protein Binding / drug effects
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Signal Transduction / drug effects
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Surface Plasmon Resonance
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Hydrazones
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Receptors, Tumor Necrosis Factor, Type I
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Small Molecule Libraries
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Thiazoles
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Tumor Necrosis Factor-alpha
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MAP Kinase Kinase 4
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Caspases