Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

被引：72

作者：

Boyd, Scott ^{[1
]}

Brookfield, Joanna L. ^{[2
]}

Critchlow, Susan E. ^{[1
]}

Cumming, Iain A. ^{[2
]}

Curtis, Nicola J. ^{[1
]}

Debreczeni, Judit ^{[1
]}

Degorce, Sebastien L. ^{[1
]}

Donald, Craig ^{[1
]}

Evans, Nicola J. ^{[3
]}

Groombridge, Sam ^{[1
]}

Hopcroft, Philip ^{[1
]}

Jones, Neil P. ^{[3
]}

Kettle, Jason G. ^{[1
]}

Lamont, Scott ^{[1
]}

Lewis, Hilary J. ^{[1
]}

MacFaull, Philip ^{[1
]}

McLoughlin, Sheila B. ^{[2
]}

Rigoreau, Laurent J. M. ^{[2
]}

Smith, James M. ^{[2
]}

St-Gallay, Steve ^{[1
]}

Stock, Julie K. ^{[3
]}

Turnbull, Andrew P. ^{[3
]}

Wheatley, Edward R. ^{[3
]}

Winter, Jon ^{[1
]}

Wingfield, Jonathan ^{[1
]}

机构：

[1] AstraZeneca, Oncol Innovat Med Unit, Macclesfield SK10 4TG, Cheshire, England

[2] CRT Discovery Labs, Cambridge CB22 3AT, England

[3] UCL, Wolfson Inst Biomed Res, CRT Discovery Labs, London WC1E 6BT, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 08期

关键词：

KEY GLYCOLYTIC ENZYME; 6-PHOSPHOFRUCTO-2-KINASE PFKFB3; CANCER; PHOSPHOFRUCTOKINASE; EXPRESSION; FAMILY;

D O I：

10.1021/acs.jmedchem.5b00352

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.

引用

页码：3611 / 3625

页数：15

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