A Novel Small-molecule TNF{alpha} Inhibitor Attenuates Inflammation in a Hepatitis Mouse Model [Cell Biology]

March 14th, 2014 by Ma, L., Gong, H., Zhu, H., Ji, Q., Su, P., Liu, P., Cao, S., Yao, J., Jiang, L., Han, M., Ma, X., Xiong, D., Luo, H. R., Wang, F., Zhou, J., Xu, Y.

Over-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 (IC50=8.73μM) 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.