Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers

Anthony, NG, Baiget, J, Berretta, G, Boyd, M, Breen, D, Edwards, J, Gamble, C, Gray, AI, Harvey, AL, Hatziieremia, S, Ho, KH, Huggan, JK, Lang, S, Llona-Minguez, S, Luo, JL, McIntosh, K, Paul, A, Plevin, RJ, Robertson, MN, Scott, R, Suckling, CJ, Sutcliffe, OB, Young, LC and Mackay, SP (2017) Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. Journal of Medicinal Chemistry, 60 (16). pp. 7043-7066. ISSN 0022-2623

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Official URL: http://pubs.acs.org/journal/jmcmar

Abstract

© 2017 American Chemical Society. IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical 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. 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 noncanonical 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 characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.

Item Type:	Article
Peer-reviewed:	Yes
Date Deposited:	08 Nov 2017 10:12
Publisher:	American Chemical Society
Additional Information:	This is an Open Access article published in Journal of Medicinal Chemistry, published by and copyright American Chemical Society.
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, DEPENDENT TRANSCRIPTION, PROSTATE-CANCER, CRYSTAL-STRUCTURE, BETA, ACTIVATION, EXPRESSION, DESIGN, POTENT, GENE, INFLAMMATION, Cell Line, Tumor, Animals, Humans, Mice, Pyrimidines, Pyrroles, Protein Isoforms, Protein Kinase Inhibitors, Signal Transduction, Structure-Activity Relationship, Drug Design, I-kappa B Kinase, NF-kappa B p52 Subunit, Biomarkers, Pharmacological, Molecular Dynamics Simulation, Molecular Docking Simulation, Animals, Biomarkers, Pharmacological, Cell Line, Tumor, Drug Design, Humans, I-kappa B Kinase, Mice, Molecular Docking Simulation, Molecular Dynamics Simulation, NF-kappa B p52 Subunit, Protein Isoforms, Protein Kinase Inhibitors, Pyrimidines, Pyrroles, Signal Transduction, Structure-Activity Relationship, 0304 Medicinal And Biomolecular Chemistry, 1115 Pharmacology And Pharmaceutical Sciences, 0305 Organic Chemistry, Medicinal & Biomolecular Chemistry
URI:	https://e-space.mmu.ac.uk/id/eprint/619397
DOI:	https://doi.org/10.1021/acs.jmedchem.7b00484
ISSN	0022-2623

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