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

Nahoum G. Anthony, Jessica Baiget, Giacomo Berretta, Marie Boyd, David Breen, Joanne Edwards, Carly Gamble, Alexander I. Gray, Alan L. Harvey, Sophia Hatziieremia, Ka Ho Ho, Judith K. Huggan, Stuart Lang, Sabin Llona-Minguez, Jia Lin Luo, Kathryn McIntosh, Andrew Paul, Robin J. Plevin, Murray N. Robertson, Rebecca Scott & 4 others Colin J. Suckling, Oliver Brook Sutcliffe, Louise C. Young, Simon P. MacKay

Research output: Contribution to journalArticle

3 Citations (Scopus)

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. 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.
LanguageEnglish
Pages7043-7066
Number of pages24
JournalJournal of Medicinal Chemistry
Volume60
Issue number16
Early online date24 Jul 2017
DOIs
Publication statusE-pub ahead of print - 24 Jul 2017

Fingerprint

Protein Isoforms
Phosphotransferases
Biomarkers
NF-kappa B
Phosphorylation

Keywords

  • IKKα
  • NF-kB pathway
  • inhibitors
  • U2OS cells

Cite this

Anthony, Nahoum G. ; Baiget, Jessica ; Berretta, Giacomo ; Boyd, Marie ; Breen, David ; Edwards, Joanne ; Gamble, Carly ; Gray, Alexander I. ; Harvey, Alan L. ; Hatziieremia, Sophia ; Ho, Ka Ho ; Huggan, Judith K. ; Lang, Stuart ; Llona-Minguez, Sabin ; Luo, Jia Lin ; McIntosh, Kathryn ; Paul, Andrew ; Plevin, Robin J. ; Robertson, Murray N. ; Scott, Rebecca ; Suckling, Colin J. ; Sutcliffe, Oliver Brook ; Young, Louise C. ; MacKay, Simon P. / Inhibitory Kappa B kinase α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 16. pp. 7043-7066.
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Inhibitory Kappa B kinase α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. / Anthony, Nahoum G.; Baiget, Jessica; Berretta, Giacomo; Boyd, Marie; Breen, David; Edwards, Joanne; Gamble, Carly; Gray, Alexander I.; Harvey, Alan L.; Hatziieremia, Sophia; Ho, Ka Ho; Huggan, Judith K.; Lang, Stuart; Llona-Minguez, Sabin; Luo, Jia Lin; McIntosh, Kathryn; Paul, Andrew; Plevin, Robin J.; Robertson, Murray N.; Scott, Rebecca; Suckling, Colin J.; Sutcliffe, Oliver Brook; Young, Louise C.; MacKay, Simon P.

In: Journal of Medicinal Chemistry, Vol. 60, No. 16, 24.07.2017, p. 7043-7066.

Research output: Contribution to journalArticle

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T1 - Inhibitory Kappa B kinase α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers

AU - Anthony, Nahoum G.

AU - Baiget, Jessica

AU - Berretta, Giacomo

AU - Boyd, Marie

AU - Breen, David

AU - Edwards, Joanne

AU - Gamble, Carly

AU - Gray, Alexander I.

AU - Harvey, Alan L.

AU - Hatziieremia, Sophia

AU - Ho, Ka Ho

AU - Huggan, Judith K.

AU - Lang, Stuart

AU - Llona-Minguez, Sabin

AU - Luo, Jia Lin

AU - McIntosh, Kathryn

AU - Paul, Andrew

AU - Plevin, Robin J.

AU - Robertson, Murray N.

AU - Scott, Rebecca

AU - Suckling, Colin J.

AU - Sutcliffe, Oliver Brook

AU - Young, Louise C.

AU - MacKay, Simon P.

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N2 - 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. 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.

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KW - NF-kB pathway

KW - inhibitors

KW - U2OS cells

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DO - 10.1021/acs.jmedchem.7b00484

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SP - 7043

EP - 7066

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -