title: Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson's disease.
abstract: Research by Klein and co-workers suggests that the inhibition of GSK-3beta by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3beta, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3beta inhibition, only ligands with a Ki value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3beta-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of alpha-Syn protein expression. We conclude that the GSK-3beta inhibitors described herein offer promise in defending cells against MPP+-induced neurotoxicity and that such compounds will be valuable to explore in animal models of Parkinson's disease as well as in other Tau-related neurodegenerative disease states.
authors.affiliation: Drug Discovery Program, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, Illinois 60612, USA. kozikowa@uic.edu
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Irina N
authors.initials: IN
authors.lastname: Gaisina
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
authors.forename: LaShaunda T
authors.initials: LT
authors.lastname: King
authors.forename: Sylvie Y
authors.initials: SY
authors.lastname: Blond
authors.forename: Tetyana
authors.initials: T
authors.lastname: Duka
authors.forename: Milan
authors.initials: M
authors.lastname: Rusnak
authors.forename: Anita
authors.initials: A
authors.lastname: Sidhu
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010300:Parkinson Disease / Q000378:metabolism*; D010766:Phosphorylation; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3