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

ABSTRACT

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