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

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

  • J Med Chem. 2017 Aug 24;60(16):7043-7066. doi: 10.1021/acs.jmedchem.7b00484.
Nahoum G Anthony 1,  Jessica Baiget 1,  Giacomo Berretta 1,  Marie Boyd 1,  David Breen 2,  Joanne Edwards 3,  Carly Gamble 1,  Alexander I Gray 1,  Alan L Harvey 1,  Sophia Hatziieremia 1,  Ka Ho Ho 1,  Judith K Huggan 1,  Stuart Lang 2,  Sabin Llona-Minguez 1,  Jia Lin Luo 1,  Kathryn McIntosh 1,  Andrew Paul 1,  Robin J Plevin 1,  Murray N Robertson 1,  Rebecca Scott 1,  Colin J Suckling 2,  Oliver B Sutcliffe 1,  Louise C Young 1,  Simon P Mackay 1
Affiliations

Affiliations

  • 1 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • 2 WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, Scotland, United Kingdom.
  • 3 Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow , Garscube Estate, Switchback Road, Glasgow G61 1QH, Scotland, United Kingdom.
PMID: 28737909 DOI: 10.1021/acs.jmedchem.7b00484
Abstract

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.

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