title: A novel small-molecule tumor necrosis factor α inhibitor attenuates inflammation in a hepatitis mouse model.
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.
authors.affiliation: From the State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Haiyan
authors.initials: H
authors.lastname: Gong
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhu
authors.forename: Qing
authors.initials: Q
authors.lastname: Ji
authors.forename: Pei
authors.initials: P
authors.lastname: Su
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Shannan
authors.initials: S
authors.lastname: Cao
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Yao
authors.forename: Linlin
authors.initials: L
authors.lastname: Jiang
authors.forename: Mingzhe
authors.initials: M
authors.lastname: Han
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Ma
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Zhou
authors.forename: Yuanfu
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006520:Hepatitis, Animal / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D019169:Jurkat Cells; D020014:K562 Cells; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D006835:Hydrazones; D047888:Receptors, Tumor Necrosis Factor, Type I; D054852:Small Molecule Libraries; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4; D020169:Caspases
keywords: Cell Death; Cell Signaling; Computer Modeling; Inflammation; Small Molecules; Surface Plasmon Resonance (SPR); Tumor Necrosis Factor (TNF)