GSK-3 inhibition: achieving moderate efficacy with high selectivity.
Inhibiting glycogen synthase kinase-3 (GSK-3) activity has become an attractive approach for treatment of neurodegenerative and psychiatric disorders. Diverse GSK-3 inhibitors have been reported and used in cellular and in vivo models. A major challenge, however, is achieving selectivity. In addition, it is increasingly recognized that a moderate inhibition of a cellular target, particularly for long-term treatment, provides more favorable outcome than complete inhibition. Substrate competitive inhibitors can fulfill the requirement for selectivity and allow fine tuning of the degree of inhibition. Here we describe the therapeutic potential of GSK-3 inhibitors and highlight our progress in the development of substrate competitive inhibitors. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Limor
L
Avrahami
Avital
A
Licht-Murava
Miriam
M
Eisenstein
Hagit
H
Eldar-Finkelman
D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D001523:Mental Disorders / Q000201:enzymology / Q000517:prevention & control; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000517:prevention & control; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary
C509073:N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha