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

Dulce Maroni, Sandeep Rana, Chandrani Mukhopadhyay, Amarnath Natarajan, Mayumi Naramura

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)319-324
Number of pages6
JournalImmunology Letters
Volume168
Issue number2
DOIs
StatePublished - Dec 1 2015

Keywords

  • Bone marrow-derived macrophages
  • IKKβ inhibitor
  • Inflammatory cytokines
  • LPS
  • NF-κB

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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