Anthony, N. G. et al. (2017) Inhibitory Kappa B kinse α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. Journal of Medicinal Chemistry, 60(16), pp. 7043-7066. (doi: 10.1021/acs.jmedchem.7b00484) (PMID:28737909) (PMCID:PMC5578373)
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Abstract
IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterised. The role of IKKα in the non-canonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ, until now. Herein, we report for the first time a series of novel, potent and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the non-canonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterise the role of IKKα in cellular signalling, to dissect this from IKKβ and validate it in its own right as a target in inflammatory diseases.
Item Type: | Articles |
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Additional Information: | Also funded by Prostate Cancer UK, grant no. PG12-27 to Strathclyde University. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Edwards, Professor Joanne and Gray, Mr Alexander and Hatziieremia, Dr Sophia and Boyd, Dr Marie |
Authors: | Anthony, N. G., Baiget, J., Berretta, G., Boyd, M., Breen, D., Edwards, J., Gamble, C., Gray, A. I., Harvey, A. L., Hatziieremia, S., Ho, K. H., Huggan, J. K., Lang, S., Llona-Minguez, S., Luo, J. L., McIntosh, K., Paul, A., Plevin, R. J., Robertson, M. N., Scott, R., Suckling, C. J., Sutcliffe, O. B., Young, L. C., and Mackay, S. P. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
Journal Name: | Journal of Medicinal Chemistry |
Publisher: | American Chemical Society |
ISSN: | 0022-2623 |
ISSN (Online): | 1520-4804 |
Published Online: | 24 July 2017 |
Copyright Holders: | Copyright © 2017 American Chemical Society |
First Published: | First published in Journal of Medicinal Chemistry 60(16): 7043-7066 |
Publisher Policy: | Reproduced under a Creative Commons license |
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