From In Vitro to In Cellulo: Evaluation of Anti-TNFα Activity of a New Series of Small Molecules

The Tumor Necrosis Factor alpha (TNFa) is a relevant clinical target for the treatment of chronic inflammatory diseases as rheumatoid arthritis or Crohn’s disease. Anti-TNFa biotherapies are used for the treatment of these diseases. They considerably improve patient living conditions but they are not without drawbacks. They cause side effects like accrue risk of infection, some patient develop resistance to these biotherapies and they are expensive. Small molecules inhibitors of TNFa would present fewer disadvantages than existing biotherapies, less side effects, no resistance, oral administration and would probably lead to less expensive treatments. Today only few small molecules are known as direct inhibitors of TNFa, SPD304 was the first small molecule described by He et al in 2005. None of these molecules showed both an efficient activity and a low toxicity, necessary to yield them into clinical trial. The Laboratory GBA of Cnam has set-up a program aiming at finding new small molecules inhibitors of TNFa. A preview in silico docking study led to the identification of potential anti-TNFa molecules. Based on the docking results, new small molecules have been designed, synthetized and biologically evaluated. Herein we describe the biological evaluation of a series of thirty new synthetized compounds for their capacity to inhibit the TNFa. These molecules were evaluated in vitro using two different immuno-assays (binding and shifting) and cell tests on two different cell lines.