publications

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

Gururaja TL, Yung S, Ding R, Huang J, Zhou X, McLaughlin J, Daniel-Issakani S, Singh R, Cooper RD, Payan DG, Masuda ES, Kinoshita T.

1: Chem Biol. 2007 Oct;14(10):1105-18.

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

PMID: 17961823 [PubMed - in process]