Anti-angiogenic potential of small molecular inhibitors of cyclin dependent kinases in vitro.
Small molecular kinase inhibitors are promising novel drugs. Initially, they were designed for the highest possible specificity. Recently, this concept has been challenged by multikinase inhibitors, which are clinically more potent. This change of paradigm calls for re-examination of already known compounds in different functional contexts. We have compared 6 reported structurally different inhibitors of cyclin-dependent kinases (Cdks) regarding their functional effects on endothelial cells (proliferation, cell cycle, apoptosis, migration, tube formation), as well as their actions on some kinases (AKT, p38, ERK1/2, c-src, GSK3β). Only some of these compounds had anti-angiogenic effects in concentrations up to 10 μM (aminopurvalanol, indirubin-3'-monoxime, and alsterpaullone), depending on their kinase profile. Interestingly, the impact of the compounds on Cdks seemed to be of minor importance, as compared to other mechanisms. Aminopurvalanol, indirubin-3'-monoxime, and alsterpaullone might turn out as interesting scaffolds for the development of novel anti-angiogenic drugs.
Zahler
Stefan
S
Department of Pharmacy, Center for System Based Drug Research, University of Munich, Butenandtstr. 5-13, 81377 Munich, Germany. stefan.zahler@cup.uni-muenchen.de
Liebl
Johanna
J
Fürst
Robert
R
Vollmar
Angelika M
AM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020868:Gene Silencing / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018716:Molecular Mimicry / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D001973:Bromodeoxyuridine