title: A quinoxaline urea analog uncouples inflammatory and pro-survival functions of IKKβ.
abstract: Activation of the NF-κB pathway is causally linked to initiation and progression of diverse cancers. Therefore, IKKβ, the key regulatory kinase of the canonical NF-κB pathway, should be a logical target for cancer treatment. However, existing IKKβ inhibitors are known to induce paradoxical immune activation, which limits their clinical usefulness. Recently, we identified a quinoxaline urea analog 13-197 as a novel IKKβ inhibitor that delays tumor growth without significant adverse effects in xenograft tumor models. In the present study, we found that 13-197 had little effect on LPS-induced NF-κB target gene induction by primary mouse macrophages while maintaining considerable anti-proliferative activities. These characteristics may explain absence of inflammatory side effects in animals treated with 13-197. Our data also demonstrate that the inflammation and proliferation-related functions of IKKβ can be uncoupled, and highlight the utility of 13-197 to dissect these downstream pathways.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Dulce
authors.initials: D
authors.lastname: Maroni
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Rana
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Chandrani
authors.initials: C
authors.lastname: Mukhopadhyay
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: mnaramura@unmc.edu.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011810:Quinoxalines / Q000494:pharmacology*
chemical_list: C584232:13-197 compound; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010671:Phenylurea Compounds; D011810:Quinoxalines; D051550:I-kappa B Kinase
keywords: Bone marrow-derived macrophages; IKKβ inhibitor; Inflammatory cytokines; LPS; NF-κB