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.

IKKβ在经典核因子κB（NF-κB）通路中发挥核心作用，该通路已被广泛深入表征。IKKα在非经典NF-κB通路中的功能，以及其作为与IKKβ组成的复合物在经典通路中的作用，目前尚未得到充分阐明。造成这一研究现状的主要原因之一，是缺乏可选择性靶向IKKα且相较于IKKβ具有特异性的化学工具分子。本文首次报道了一系列新型、强效且高选择性的IKKα抑制剂。我们通过实验证实，此类化合物可在U2OS细胞中实现有效的靶标结合与选择性：其可抑制非经典NF-κB通路中IKKα介导的p100磷酸化，同时不会影响经典通路中IKKβ依赖的IκBα降解。这些化合物是首批可用于进一步解析IKKα在细胞信号转导中的功能、将其与IKKβ的生物学作用区分开来，并独立验证其作为炎症性疾病治疗靶点可行性的化学工具分子。