title: A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1.
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.
authors.affiliation: Rigel Pharmaceuticals, Incorporated, 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. tgururaja@rigel.com
authors.forename: Tarikere L
authors.initials: TL
authors.lastname: Gururaja
authors.forename: Stephanie
authors.initials: S
authors.lastname: Yung
authors.forename: Rongxian
authors.initials: R
authors.lastname: Ding
authors.forename: Jianing
authors.initials: J
authors.lastname: Huang
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhou
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.forename: Sarkiz
authors.initials: S
authors.lastname: Daniel-Issakani
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Robin D G
authors.initials: RD
authors.lastname: Cooper
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: Esteban S
authors.initials: ES
authors.lastname: Masuda
authors.forename: Taisei
authors.initials: T
authors.lastname: Kinoshita
mesh_terms: 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
chemical_list: 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