Inhibitory Kappa B Kinase Alpha (Ikk Alpha) Inhibitors That Recapitulate Their Selectivity In Cells Against Isoform-Related Biomarkers

IKK beta plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKK alpha in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKK beta, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKK alpha over IKK beta. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKK alpha. We demonstrate effective target engagement and selectivity with IKK alpha in U2OS cells through inhibition of IKK alpha-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKK beta-dependent IKapp-B alpha loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKK alpha a in cellular signaling, to dissect this from IKK beta and to validate it in its own right as a target in inflammatory diseases.