A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1.
Chem Biol
; 14(10): 1105-18, 2007 Oct.
Article
en En
| MEDLINE
| ID: mdl-17961823
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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Bases de datos:
MEDLINE
Asunto principal:
Quinoxalinas
/
Triazoles
/
Factor de Necrosis Tumoral alfa
/
Apoptosis
/
Molécula 1 de Adhesión Intercelular
/
Receptores Tipo I de Factores de Necrosis Tumoral
/
Inhibidores Enzimáticos
/
Proteína Serina-Treonina Quinasas de Interacción con Receptores
/
Proteína de Dominio de Muerte Asociada a Receptor de TNF
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Chem Biol
Asunto de la revista:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos