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.
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.
Wagner
Jürgen
J
Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland. juergen.wagner@novartis.com
von Matt
Peter
P
Sedrani
Richard
R
Albert
Rainer
R
Cooke
Nigel
N
Ehrhardt
Claus
C
Geiser
Martin
M
Rummel
Gabriele
G
Stark
Wilhelm
W
Strauss
Andre
A
Cowan-Jacob
Sandra W
SW
Beerli
Christian
C
Weckbecker
Gisbert
G
Evenou
Jean-Pierre
JP
Zenke
Gerhard
G
Cottens
Sylvain
S
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
D007527:Isoenzymes; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C