title: Substrate competitive GSK-3 inhibitors - strategy and implications.
abstract: Glycogen synthase kinase-3 (GSK-3) is a highly conserved protein serine/threonine kinase ubiquitously distributed in eukaryotes as a constitutively active enzyme. Abnormally high GSK-3 activity has been implicated in several pathological disorders, including diabetes and neuron degenerative and affective disorders. This led to the hypothesis that inhibition of GSK-3 may have therapeutic benefit. Most GSK-3 inhibitors developed so far compete with ATP and often show limited specificity. Our goal is to develop inhibitors that compete with GSK-3 substrates, as this type of inhibitor is more specific and may be useful for clinical applications. We have employed computational, biochemical, and molecular analyses to gain in-depth understanding of GSK-3's substrate recognition. Here we argue that GSK-3 is a promising drug discovery target and describe the strategy and practice for developing specific substrate-competitive inhibitors of GSK-3.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. heldar@post.tau.ac.il
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.forename: Avital
authors.initials: A
authors.lastname: Licht-Murava
authors.forename: Shmuel
authors.initials: S
authors.lastname: Pietrokovski
authors.forename: Miriam
authors.initials: M
authors.lastname: Eisenstein
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3