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
Journal of Medicinal Chemistry2009Vol. 52(20), pp. 6193–6196
Citations Over TimeTop 10% of 2009 papers
Jürgen Wagner, Peter Matt, Richard Sedrani, Rainer Albert, Nigel G. Cooke, Claus Ehrhardt, Martin Geiser, Gabriele Rummel, Wilhelm Stark, André Strauss, Sandra W. Cowan‐Jacob, Christian Beerli, Gisbert Weckbecker, Jean-Pierre Evenou, Gerhard Zenke, Sylvain Cottens
Abstract
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 PKCalpha.
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