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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.

Abstract

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.

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Figure 1: Schematic structure of NF-κB and IκB proteins.
Figure 2: Schematic representation of the two NF-κB signalling pathways.

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Correspondence to Michael Karin or Q. May Wang.

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DATABASES

LocusLink

c-FLIP

ICAM-1

IKK-α

IKK-β

IKK-ε

IKK-γ

IL-6

NF-κB1

NF-κB2

PPAR-γ

RANK

Rel

RelA

RelB

TBK1

TNFR1

VCAM-1

VEGF

Online Mendelian Inheritance in Man

Inflammatory bowel disease

Glossary

ANKYRIN

A type of protein structural motif composed of a helix-turn-helix that mediates protein–protein interactions.

PHOSPHORYLATION

A type of protein modification involving the covalent addition of phosphate groups to serine, threonine or tyrosine residues.

UBIQUITINATION

A type of protein modification involving the covalent addition of ubiquitin, a small protein, to lysine groups. Poly-ubiquitination targets proteins for degradation.

OSTEOCLASTS

Bone-degrading cells, derived from macrophages.

PROSTAGLANDINS

Derivatives of arachidonic acid (a fatty acid) that can trigger various physiological responses, including inflammation and pain.

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Karin, M., Yamamoto, Y. & Wang, Q. The IKK NF-κB system: a treasure trove for drug development. Nat Rev Drug Discov 3, 17–26 (2004). https://doi.org/10.1038/nrd1279

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