Fibrinogen-like globe domain of human Tenascin-C (hFBG-C); A Target Enabling Package

Chronic activation of the innate immune system by the damage-associated molecular pattern FBG-C (C-terminal fibrinogen-like globe domain of Tenascin-C) contributes to a variety of inflammatory diseases including arthritis, systemic sclerosis, and cancer. This TEP summarizes the first reported efforts to develop small-molecule FBG-C binders, with the aim to disrupt FBG-C-mediated pro-inflammatory protein-protein interactions (PPIs). We present the soluble expression of disulphide-containing human FBG-C (hFBG-C) in E. coli, the novel structure of hFBG-C, and preliminary chemical matter against hFBG-C derived from a crystallographic fragment screen. Finally, we introduce two robustly validated cellular assays, in either immortalized monocytes or primary human macrophages, which provide a route to development of small molecules which inhibit hFBG-C-activated inflammation.