Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells.
The Wnt pathway is involved in cellular processes linked to either proliferation or differentiation. Therefore small molecules offer an attractive opportunity to modulate this pathway, whereas the key enzyme GSK-3beta is of special interest. In this study, non-symmetrically substituted indolylmaleimides have been synthesized and their ability to function as GSK-3beta inhibitors has been investigated in a human neural progenitor cell line. Among the newly synthesized compounds, the substance IM-12 showed a significant activity in several biological tests which was comparable or even outplayed the effects of the known GSK-3beta inhibitor SB-216763. Furthermore the treatment of human neural progenitor cells with IM-12 resulted in an increase of neuronal cells. Therefore we conclude that indolylmaleimides act via the canonical Wnt signalling pathway by inhibition of the key enzyme GSK-3beta.
Schmöle
Anne-Caroline
AC
Albrecht-Kossel-Institute for Neuroregeneration (AKos), Center for Mental Health, University of Rostock, Gehlsheimer Str. 20, D-18147 Rostock, Germany.
Brennführer
Anne
A
Karapetyan
Gnuni
G
Jaster
Robert
R
Pews-Davtyan
Anahit
A
Hübner
Rayk
R
Ortinau
Stefanie
S
Beller
Matthias
M
Rolfs
Arndt
A
Frech
Moritz J
MJ
D002454:Cell Differentiation; D049109:Cell Proliferation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C554531:3-(4-fluorophenylethylamino)-1-methyl-4-(2-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C417521:SB 216763; D051153:Wnt Proteins; D051176:beta Catenin; C043592:maleimide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3