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.

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.

Publication types

  • Congress

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Epithelial Cells / cytology
  • Epithelial Cells / pathology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Lung / cytology
  • Lung / pathology
  • Quinoxalines / pharmacology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Small Molecule Libraries
  • TNF Receptor-Associated Death Domain Protein / genetics
  • TNF Receptor-Associated Death Domain Protein / metabolism*
  • Triazoles / pharmacology*
  • Tumor Necrosis Factor-alpha*

Substances

  • Enzyme Inhibitors
  • Quinoxalines
  • Receptors, Tumor Necrosis Factor, Type I
  • Small Molecule Libraries
  • TNF Receptor-Associated Death Domain Protein
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Receptor-Interacting Protein Serine-Threonine Kinases