Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 802–819 |
| Number of pages | 18 |
| Journal | British Journal of Pharmacology |
| Volume | 165 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2011 |
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Keywords
- inhibitory kappa B kinase
- inflammation
- protein-protein interactions
- kinase inhibitors
- nuclear factor kappa B
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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 journal › Article
TY - JOUR
T1 - Inhibitory kappa B kinases as targets for pharmacological regulation
AU - Gamble, Carly
AU - McIntosh, Kathryn
AU - Scott, Rebecca
AU - Ho, Ka Ho
AU - Plevin, Robin
AU - Paul, Andrew
N1 - © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - inhibitory kappa B kinase
KW - inflammation
KW - protein-protein interactions
KW - kinase inhibitors
KW - nuclear factor kappa B
U2 - 10.1111/j.1476-5381.2011.01608.x
DO - 10.1111/j.1476-5381.2011.01608.x
M3 - Article
VL - 165
SP - 802
EP - 819
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 4
ER -