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

被引：36

作者：

Anthony, Nahoum G. ^{[1
]}

Baiget, Jessica ^{[1
]}

Berretta, Giacomo ^{[1
]}

Boyd, Marie ^{[1
]}

Breen, David

Edwards, Joanne ^{[3
]}

Gamble, Carly ^{[1
]}

Gray, Alexander I. ^{[1
]}

Harvey, Alan L. ^{[1
]}

Hatziieremia, Sophia ^{[1
]}

Ho, Ka Ho ^{[1
]}

Huggan, Judith K. ^{[1
]}

Lang, Stuart ^{[2
]}

Llona-Minguez, Sabin ^{[1
]}

Luo, Jia Lin ^{[1
]}

McIntosh, Kathryn ^{[1
]}

Paul, Andrew ^{[1
]}

Plevin, Robin J. ^{[1
]}

Robertson, Murray N. ^{[1
]}

Scott, Rebecca ^{[1
]}

Suckling, Colin J. ^{[2
]}

Sutcliffe, Oliver B. ^{[1
]}

Young, Louise C. ^{[1
]}

Mackay, Simon P. ^{[1
]}

机构：

[1] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, 161 Cathedral St, Glasgow G4 0NR, Lanark, Scotland

[2] Univ Strathclyde, WestCHEM Dept Pure & Appl Chem, 295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland

[3] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Switchback Rd, Glasgow G61 1QH, Lanark, Scotland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 16期

关键词：

DEPENDENT TRANSCRIPTION; PROSTATE-CANCER; INFLAMMATORY RESPONSES; CRYSTAL-STRUCTURE; BETA; ACTIVATION; EXPRESSION; DESIGN; POTENT; GENE;

D O I：

10.1021/acs.jmedchem.7b00484

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

IKK beta plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKK alpha in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKK beta, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKK alpha over IKK beta. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKK alpha. We demonstrate effective target engagement and selectivity with IKK alpha in U2OS cells through inhibition of IKK alpha-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKK beta-dependent IKapp-B alpha loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKK alpha a in cellular signaling, to dissect this from IKK beta and to validate it in its own right as a target in inflammatory diseases.

引用

页码：7043 / 7066

页数：24

共 47 条

[1] B-cell-derived lymphotoxin promotes castration-resistant prostate cancer [J].