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

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• 作者：Jrgen Wagner ; Peter von Matt ; Richard Sedrani ; Rainer Albert ; Nigel Cooke ; Claus Ehrhardt ; Martin Geiser ; Gabriele Rummel ; Wilhelm Stark ; Andre Strauss ; Sandra W. Cowan-Jacob ; Christian Beerli ; Gisber
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 22, 2009
• 年：2009
• 卷：52
• 期：20
• 页码：6193-6196
• 全文大小：761K
• 年卷期：v.52,no.20(October 22, 2009)
• ISSN：1520-4804

文摘

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 PKCα.