Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers

IKKβ
plays a central role in the canonical NF-kB pathway, which has been
extensively characterized. The role of IKKα in the noncanonical
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 noncanonical 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 characterize
the role of IKKα in cellular signaling, to dissect this from
IKKβ and to validate it in its own right as a target in inflammatory
diseases.