Late pre-clinical developement of CD40-TRAF6 inhibitors (TRAF-STOPs) part I: Go - No Go project

Blocking the co-stimulatory CD40L-CD40 dyad reduces atherosclerosis. We found that the interaction between CD40 and TNF-receptor-associated factor 6 (TRAF6) is the driving force for atherosclerosis. Using virtual ligand screening, we identified several small molecule inhibitors termed TRAF-STOPs that were modeled to bind to the CD40-binding domain of TRAF6. Two TRAF-STOPs significantly reduce existing atherosclerosis, improve glucose tolerance and insulin sensitivity in mice, and ameliorate multiple sclerosis. Here we pursue the hypothesis that these TRAF-STOPs are candidates to pass the translational pipeline towards a clinical application to treat chronic inflammatory diseases, including atherosclerosis. Dose finding studies, toxicity and pharmacological safety studies as well as pharmacodynamic studies will be performed, the pharmacological properties will be improved and the proof of the specificity of these small molecule inhibitors will be established.