Discovery of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a Potent and Selective Inhibitor of Protein Kinase C Isotypes

被引：113

作者：

Wagner, Juergen ^{[1
]}

von Matt, Peter ^{[1
]}

Sedrani, Richard ^{[1
]}

Albert, Rainer ^{[1
]}

Cooke, Nigel ^{[1
]}

Ehrhardt, Claus ^{[1
]}

Geiser, Martin ^{[1
]}

Rummel, G'abriele ^{[1
]}

Stark, Wilhelm ^{[1
]}

Strauss, Andre ^{[1
]}

Cowan-Jacob, Sandra W. ^{[1
]}

Beerli, Christian ^{[1
]}

Weckbecker, Gisbert ^{[1
]}

Evenou, Jean-Pierre ^{[1
]}

Zenke, Gerhard ^{[1
]}

Cottens, Sylvain ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 20期

关键词：

PKC-THETA;

D O I：

10.1021/jm901108b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel maleimide-based inhibitors of protein kinase C (PKC) were designed, synthesized, and evaluated. AEB071 (1) was found to be a potent, selective inhibitor of classical and novel PKC isotypes. 1 is a highly efficient immunomodulator, acting via inhibition of early T cell activation. The binding mode of maleimides to PKCs, proposed by molecular modeling, was confirmed by X-ray analysis of 1 bound in the active site of PKC alpha.

引用

页码：6193 / 6196

页数：4

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