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

  • J Med Chem. 2009 Oct 22;52(20):6193-6. doi: 10.1021/jm901108b.
Jürgen Wagner  1 ,  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 ,  Gisbert Weckbecker ,  Jean-Pierre Evenou ,  Gerhard Zenke ,  Sylvain Cottens
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland. [email protected]
PMID: 19827831 DOI: 10.1021/jm901108b
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.