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

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

Affiliation

  • 1 Rigel Pharmaceuticals, Incorporated, 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. tgururaja@rigel.com
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-110203
    98.55%, TNF Receptor拮抗剂