Inhibitory Kappa B kinse α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers

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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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
Additional Information:Also funded by Prostate Cancer UK, grant no. PG12-27 to Strathclyde University.
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 (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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
497591A comprehensive multidisciplinary approach to target the inhibitory kappa B kinase pathway to discover novel therapies in prostate cancerJoanne EdwardsCancer Research UK (CRUK)C7599/A9336RI CANCER SCIENCES