Inhibitory kappa B kinases as targets for pharmacological regulation

Carly Gamble, Kathryn McIntosh, Rebecca Scott, Ka Ho Ho, Robin Plevin, Andrew Paul

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The inhibitory kappa B kinases (IKKs) are well recognised as key regulators of the Nuclear Factor kappa B (NFκB) cascade and as such represent a point of convergence for many extracellular agents that activate this pathway. The IKKs generally serve to transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes but also play a key role in the pathogenesis of a number of human diseases. Therefore, the catalytic IKKs represent attractive targets for intervention with small molecule kinase inhibitors. IKK isoforms are assembled as variable multi-subunit IKK complexes that regulate not only NFκB dimers, but also protein substrates out-with this cascade. Consequently, close consideration of how these individual complexes transduce extracellular signals and more importantly what impact small molecule inhibitors of the IKKs have on functional outcomes are demanded. A number of ATP-competitive IKKβ-selective inhibitors have been developed but have demonstrated a lack of activity against IKKα. A number of these chemicals have also exhibited detrimental outcomes such as cellular toxicity and immuno-suppression. The impact of small molecule inhibitors of IKK catalytic activity will therefore be reappraised, examining the advantages and potential disadvantages to this type of intervention strategy in the treatment of diseases such as arthritis, intestinal inflammation and cancer. Furthermore, we will outline some emerging strategies, particularly the disruption of protein-protein interactions within the IKK complex, as an alternative route towards the development of novel pharmacological agents. Whether these alternatives may negate the limitations of Adenosine Triphosphate (ATP)-competitive molecules and potentially avoid the issues of toxicity will be discussed.
LanguageEnglish
Pages802–819
Number of pages18
JournalBritish Journal of Pharmacology
Volume165
Issue number4
DOIs
Publication statusPublished - 2011

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Phosphotransferases
Pharmacology
Adenosine Triphosphate
Intestinal Neoplasms
Proteins
NF-kappa B
Arthritis
Protein Isoforms
Inflammation
Growth

Keywords

  • inhibitory kappa B kinase
  • inflammation
  • protein-protein interactions
  • kinase inhibitors
  • nuclear factor kappa B

Cite this

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abstract = "The inhibitory kappa B kinases (IKKs) are well recognised as key regulators of the Nuclear Factor kappa B (NFκB) cascade and as such represent a point of convergence for many extracellular agents that activate this pathway. The IKKs generally serve to transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes but also play a key role in the pathogenesis of a number of human diseases. Therefore, the catalytic IKKs represent attractive targets for intervention with small molecule kinase inhibitors. IKK isoforms are assembled as variable multi-subunit IKK complexes that regulate not only NFκB dimers, but also protein substrates out-with this cascade. Consequently, close consideration of how these individual complexes transduce extracellular signals and more importantly what impact small molecule inhibitors of the IKKs have on functional outcomes are demanded. A number of ATP-competitive IKKβ-selective inhibitors have been developed but have demonstrated a lack of activity against IKKα. A number of these chemicals have also exhibited detrimental outcomes such as cellular toxicity and immuno-suppression. The impact of small molecule inhibitors of IKK catalytic activity will therefore be reappraised, examining the advantages and potential disadvantages to this type of intervention strategy in the treatment of diseases such as arthritis, intestinal inflammation and cancer. Furthermore, we will outline some emerging strategies, particularly the disruption of protein-protein interactions within the IKK complex, as an alternative route towards the development of novel pharmacological agents. Whether these alternatives may negate the limitations of Adenosine Triphosphate (ATP)-competitive molecules and potentially avoid the issues of toxicity will be discussed.",
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Inhibitory kappa B kinases as targets for pharmacological regulation. / Gamble, Carly; McIntosh, Kathryn; Scott, Rebecca; Ho, Ka Ho; Plevin, Robin; Paul, Andrew.

In: British Journal of Pharmacology, Vol. 165, No. 4, 2011, p. 802–819.

Research output: Contribution to journalArticle

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AU - Gamble, Carly

AU - McIntosh, Kathryn

AU - Scott, Rebecca

AU - Ho, Ka Ho

AU - Plevin, Robin

AU - Paul, Andrew

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