A quinoxaline urea analog uncouples inflammatory and pro-survival functions of IKKβ

Activation of the NF-kappa B pathway is causally linked to initiation and progression of diverse cancers. Therefore, IKK beta, the key regulatory kinase of the canonical NF-kappa B pathway, should be a logical target for cancer treatment. However, existing IKK beta 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 IKK beta 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-kappa B 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 IKK beta can be uncoupled, and highlight the utility of 13-197 to dissect these downstream pathways. (C) 2015 Elsevier B.V. All rights reserved.