A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1

  • Chem Biol. 2007 Oct;14(10):1105-18. doi: 10.1016/j.chembiol.2007.08.012.
Tarikere L Gururaja  1 ,  Stephanie Yung ,  Rongxian Ding ,  Jianing Huang ,  Xiulan Zhou ,  John McLaughlin ,  Sarkiz Daniel-Issakani ,  Rajinder Singh ,  Robin D G Cooper ,  Donald G Payan ,  Esteban S Masuda ,  Taisei Kinoshita
Affiliations
  • 1. Rigel Pharmaceuticals, Incorporated, 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. [email protected]
PMID: 17961823 DOI: 10.1016/j.chembiol.2007.08.012
Abstract

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.

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