A Class of Small Molecules that Inhibit TNFα-Induced Survival and Death Pathways via Prevention of Interactions between TNFαRI, TRADD, and RIP1

SummarySmall-molecule library screening to find compounds that inhibit TNFα-induced, but not interleukin 1β (IL-1β)-induced, intercellular adhesion molecule 1 (ICAM-1) expression in lung epithelial cells identified a class of triazoloquinoxalines. These compounds not only inhibited the TNFα-induced nuclear factor κB (NFκB) survival pathway but also blocked death-pathway activation. Such dual activity makes them unique against other known NFκB-pathway inhibitors that inhibit only a subset of TNFα signals leading to increased TNFα-induced cytotoxicity. Interestingly, these compounds inhibited association of TNFα receptor (TNFαR) I with TNFαR-associated death domain protein (TRADD) and receptor interacting protein 1 (RIP1), the initial intracellular signaling event following TNFα stimulation. Further study showed that they blocked ligand-dependent internalization of the TNFα-TNFαR complex, thereby inhibiting most of the TNFα-induced cellular responses. Thus, compounds with a triazoloquinoxaline scaffold could be a valuable tool to investigate small molecule-based anti-TNFα therapies.