Ma, LiGong, HaiyanZhu, HaiyanJi, QingSu, PeiLiu, PengCao, ShannanYao, JianfengJiang, LinlinHan, MingzheMa, XiaotongXiong, DongshengLuo, HongboWang, FeiZhou, JiaxiXu, Yuanfu2014-11-052014Ma, Li, Haiyan Gong, Haiyan Zhu, Qing Ji, Pei Su, Peng Liu, Shannan Cao, et al. 2014. “A Novel Small-Molecule Tumor Necrosis Factor \(\alpha\) Inhibitor Attenuates Inflammation in a Hepatitis Mouse Model.” Journal of Biological Chemistry 289 (18) (March 14): 12457–12466. doi:10.1074/jbc.m113.521708. http://dx.doi.org/10.1074/jbc.M113.521708.0021-92581083-351Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13350302Over-expression 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 (CADD) 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 \((IC_{50}=8.73\mu M)\) 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.en-UScell deathcell signalinginflammationsmall moleculestumor necrosis factorcomputer modelingsurface plasmon resonanceJournal Article10.1074/jbc.M113.521708