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

• Published in: Journal of medicinal chemistry Vol. 60; no. 16; pp. 7043 - 7066
• Main Authors: 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 B, Young, Louise C, Mackay, Simon P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.08.2017; Amer Chemical Soc
• Subjects: Animals; Biomarkers, Pharmacological - metabolism; Cell Line, Tumor; Chemistry, Medicinal; Drug Design; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - chemistry; Life Sciences & Biomedicine; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; NF-kappa B p52 Subunit - metabolism; Pharmacology & Pharmacy; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - chemistry; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Signal Transduction - drug effects; Structure-Activity Relationship; ACTIVATION; DESIGN; POTENT; GENE; DEPENDENT TRANSCRIPTION; INFLAMMATORY RESPONSES; CRYSTAL-STRUCTURE; PROSTATE-CANCER; EXPRESSION; BETA
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00484

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.