Inhibitory Kappa B kinase α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers

Nahoum G. Anthony, Jessica Baiget, Giacomo Berretta, Marie Boyd, David Breen, Joanne Edwards, Carly Gamble, Alexander I. Gray, Alan L. Harvey, Sophia Hatziieremia, Ka Ho Ho, Judith K. Huggan, Stuart Lang, Sabin Llona-Minguez, Jia Lin Luo, Kathryn McIntosh, Andrew Paul, Robin J. Plevin, Murray N. Robertson, Rebecca ScottColin J. Suckling, Oliver Brook Sutcliffe, Louise C. Young, Simon P. MacKay

Research output: Contribution to journalArticle

4 Citations (Scopus)
129 Downloads (Pure)

Abstract

IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterised. The role of IKKα in the non-canonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the non-canonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterise the role of IKKα in cellular signalling, to dissect this from IKKβ and validate it in its own right as a target in inflammatory diseases.
Original languageEnglish
Pages (from-to)7043-7066
Number of pages24
JournalJournal of Medicinal Chemistry
Volume60
Issue number16
Early online date24 Jul 2017
DOIs
Publication statusE-pub ahead of print - 24 Jul 2017

    Fingerprint

Keywords

  • IKKα
  • NF-kB pathway
  • inhibitors
  • U2OS cells

Cite this