Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents

被引：29

作者：

Francis, Stuart ^{[1
]}

Croft, Daniel ^{[1
]}

Schtittelkopf, Alexander W. ^{[1
]}

Parry, Charles ^{[1
]}

Pughese, Angelo ^{[1
]}

Cameron, Ken ^{[1
]}

Claydon, Sophie ^{[1
]}

Drysdale, Martin ^{[1
,4
]}

Gardner, Claire ^{[1
]}

Gohlke, Andrea ^{[1
]}

Goodwin, Gillian ^{[1
]}

Gray, Christopher H. ^{[1
]}

Konczal, Jennifer ^{[1
]}

McDonald, Laura ^{[1
]}

Mezna, Mokdad ^{[1
]}

Pannifer, Andrew ^{[1
,5
]}

Paul, Nikki R. ^{[2
]}

Machesky, Laura ^{[2
,3
]}

McKinnon, Heather ^{[1
]}

Bower, Justin ^{[1
]}

机构：

[1] CRUK Beatson Inst, Drug Discovery Unit, Glasgow G61 1BD, Lanark, Scotland

[2] CRUK Beatson Inst, Cell Migrat Lab, Glasgow G61 1BD, Lanark, Scotland

[3] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

[4] Broad Inst, Cambridge, MA 02142 USA

[5] Med Discovery Catapult, Alderly Pk, Alderley Edge SK10 4TG, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 08期

关键词：

Virtual screening; Fragments; Drug discovery; Medicinal chemistry; Cancer; LIGAND; CANCER;

D O I：

10.1016/j.bmcl.2019.01.035

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.

引用

页码：1023 / 1029

页数：7

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