The IKK NF-κB system: a treasure trove for drug development

Key Points Gene-disruption studies provide evidence that IκB kinase (IKK) complex is essential to the activation of NF-κB signalling pathways. The two kinase subunits of the IKK complex, IKK-α and IKK-β, are viewed as therapeutic targets for development of anti-inflammatory and anticancer agents. IKK-α and IKK-β activate NF-κB pathways through distinct mechanisms. IKK-β is indispensable for phosphorylation of IκB proteins and the subsequent activation of the classical NF-κB signalling pathway. Although the kinase activity of IKK-α, but not IKK-β, is required for p100 processing, activation of the alternative NF-κB pathway, and B-cell proliferation and maturation. Recent studies indicate that certain non-steroidal anti-inflammatory drugs (NSAIDs) function as non-selective IKK inhibitors. These include aspirin, salicylates, sulindac and its analogues, and suphasalazine and its metabolites. In addition, non-selective inhibition of IKK activity by a number of immunomodulatory drugs (IMiDs), including thalidomides, cyclopentonone prostaglandins and certain antioxidants, has also been reported. No selective IKK-α inhibitors have been reported, partially because of the incomplete understanding of the role of IKK-α in NF-κB activation. On the other hand, the development of specific IKK-β inhibitors has progressed rapidly. A number of novel, small-molecule inhibitors of IKK-β have demonstrated anti-inflammatory activity in animal models. Advancement of IKK-β inhibitors into clinical development is anticipated in the near future. Nuclear factor-κB (NF-κB)/Rel transcription factors have been suspected since their discovery to play a pivotal role in chronic and acute inflammatory diseases. It now seems that aberrant regulation of NF-κB could also underlie autoimmune diseases and different types of cancer. Recently, NF-κB and the signalling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. Given the large number of major ailments in which aberrant regulation of NF-κB has been observed or is suspected, such efforts seem well justified. This review will discuss recent progress in the development of drugs that inhibit NF-κB activation, and consider their potential applications in inflammatory and autoimmune diseases, as well as cancer.