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.

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.

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Drug Discovery
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Maleimides / chemistry
  • Maleimides / metabolism
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Weight
  • Protein Kinase C / chemistry
  • Protein Kinase C / metabolism*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Quinazolines / chemistry
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Rats
  • Substrate Specificity
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Transplantation Tolerance

Substances

  • Isoenzymes
  • Maleimides
  • Protein Kinase Inhibitors
  • Pyrroles
  • Quinazolines
  • sotrastaurin
  • Protein Kinase C

Associated data

  • PDB/3IW4