A Novel Small-molecule Tumor Necrosis Factor α Inhibitor Attenuates Inflammation in a Hepatitis Mouse Model

Background: Most commercial TNF inhibitors are biomacromolecules. Results: A lead compound named C87 was identified using computer-aided drug design and could attenuate murine acute hepatitis. Conclusion: C87 was one of the first effective small-molecule inhibitors of TNF identified to date. Significance: The study highlights the effectiveness of combining virtual screening with functional assays for developing novel small-molecule TNF inhibitors. Overexpression of tumor necrosis factor (TNF) 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 TNF 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 TNF, potently inhibits TNF-induced cytotoxicity (IC50 = 8.73 m) and effectively blocks TNF-triggered signaling activities. Furthermore, by using a murine acute hepatitis model, we showed that C87 attenuates TNF-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 TNF inhibitor, which can be potentially used to treat TNF-mediated inflammatory diseases.