A quinoxaline urea analog uncouples inflammatory and pro-survival functions of IKK?.

ABSTRACT: Activation of the NF-?B pathway is causally linked to initiation and progression of diverse cancers. Therefore, IKK?, the key regulatory kinase of the canonical NF-?B pathway, should be a logical target for cancer treatment. However, existing IKK? 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? 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-?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? can be uncoupled, and highlight the utility of 13-197 to dissect these downstream pathways.

SUBMITTER: Maroni D 

PROVIDER: S-EPMC4688189 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature