for interacting with IKK; compounds that have allosteric effects on IKK structure; and compounds that interact with a specific cysteine residue (Cys-179) in the activation loop of IKKβ. ATP analogs include natural products such as β-carboline and synthetic compounds such as SC-839, which has an approximately 200-fold preference for IKKβ compared to IKKα [27, 31]. Compounds that have allosteric effects on IKK structure include BMS-345541, a synthetic compound that binds to an allosteric site on both IKKα and IKKβ and has an approximately 10-fold greater inhibitory effect on IKKβ than on IKKα [32]. Compounds that interact with Cys-179 IKKβ include thiol-reactive compounds such as parthenolide, arsenite, and certain epoxyquinoids [33–36]; these compounds’ interactions with Cys-179 are believed to interfere with phosphorylation- induced IKKβ activation because Cys-179 is located between Ser177 and Ser181, which are required for IKKβ activation in response to upstream signals such as tumor necrosis factor (TNF) and lipopolysaccharide (LPS) [37, 38]. Gene-based inhibitors can also block IKK activation. Specifically, mutations at the ATP-binding site or in the kinase activation loop can create dominant-negative IKKα and IKKβ, which are capable of blocking NF-κB activation [39–43]. Because of their distinct roles in the canonical and non-canonical NF-κB activation pathways,
