A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1.
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.
Gururaja
Tarikere L
TL
Rigel Pharmaceuticals, Incorporated, 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. tgururaja@rigel.com
Yung
Stephanie
S
Ding
Rongxian
R
Huang
Jianing
J
Zhou
Xiulan
X
McLaughlin
John
J
Daniel-Issakani
Sarkiz
S
Singh
Rajinder
R
Cooper
Robin D G
RD
Payan
Donald G
DG
Masuda
Esteban S
ES
Kinoshita
Taisei
T
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D054852:Small Molecule Libraries; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha
D004791:Enzyme Inhibitors; D011810:Quinoxalines; D047888:Receptors, Tumor Necrosis Factor, Type I; D054852:Small Molecule Libraries; D053199:TNF Receptor-Associated Death Domain Protein; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases