title: 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.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland. juergen.wagner@novartis.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wagner
authors.forename: Peter
authors.initials: P
authors.lastname: von Matt
authors.forename: Richard
authors.initials: R
authors.lastname: Sedrani
authors.forename: Rainer
authors.initials: R
authors.lastname: Albert
authors.forename: Nigel
authors.initials: N
authors.lastname: Cooke
authors.forename: Claus
authors.initials: C
authors.lastname: Ehrhardt
authors.forename: Martin
authors.initials: M
authors.lastname: Geiser
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rummel
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Stark
authors.forename: Andre
authors.initials: A
authors.lastname: Strauss
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.forename: Gisbert
authors.initials: G
authors.lastname: Weckbecker
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Evenou
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zenke
authors.forename: Sylvain
authors.initials: S
authors.lastname: Cottens
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008301:Maleimides / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D023001:Transplantation Tolerance
chemical_list: D007527:Isoenzymes; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C