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

Anthony, Nahoum G. and Baiget, Jessica and Berretta, Giacomo and Boyd, Marie and Breen, David and Edwards, Joanne and Gamble, Carly and Gray, Alexander I. and Harvey, Alan L. and Hatziieremia, Sophia and Ho, Ka Ho and Huggan, Judith K. and Lang, Stuart and Llona-Minguez, Sabin and Luo, Jia Lin and McIntosh, Kathryn and Paul, Andrew and Plevin, Robin J. and Robertson, Murray N. and Scott, Rebecca and Suckling, Colin J. and Sutcliffe, Oliver Brook and Young, Louise C. and MacKay, Simon P. (2017) Inhibitory Kappa B kinase α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. Journal of Medicinal Chemistry, 60 (16). pp. 7043-7066. ISSN 0022-2623

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    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.