Discovery of Small Molecule CD40–TRAF6 Inhibitors

The CD154–CD40 receptor complex plays a pivotal role in several inflammatory pathways. Attempts to inhibit the formation of this complex have resulted in systemic side effects. Downstream inhibition of the CD40 signaling pathway therefore seems a better way to ameliorate inflammatory disease. To relay a signal, the CD40 receptor recruits adapter proteins called tumor necrosis factor receptor-associated factors (TRAFs). CD40–TRAF6 interactions are known to play an essential role in several inflammatory diseases. We used in silico, in vitro, and in vivo experiments to identify and characterize compounds that block CD40–TRAF6 interactions. We present in detail our drug docking and optimization pipeline and show how we used it to find lead compounds that reduce inflammation in models of peritonitis and sepsis. These compounds appear to be good leads for drug development, given the observed absence of side effects and their demonstrated efficacy for peritonitis and sepsis in mouse models.