Highly potent and specific GSK-3β inhibitors that block tau phosphorylation and decrease α-synuclein protein expression in a cellular model of Parkinson's disease

Alan P. Kozikowski, Irina N. Gaisina, Pavel A. Petukhov, Jayalakshmi Sridhar, La Shaunda T. King, Sylvie Y. Blond, Tetyana Duka, Milan Rusnak, Anita Sidhu

Research output: Contribution to journalArticle

Abstract

Research by Klein and co-workers suggests that the inhibition of GSK-3β 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-3β, 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-3β inhibition, only ligands with a K. value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3β-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of α-Syn protein expression. We conclude that the GSK-3β 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.

Original languageEnglish (US)
Pages (from-to)256-266
Number of pages11
JournalChemMedChem
Volume1
Issue number2
DOIs
StatePublished - Feb 1 2006

Keywords

  • CNS
  • Drug design
  • Glycogen synthase kinase-3β
  • Inhibitors
  • Phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Kozikowski, A. P., Gaisina, I. N., Petukhov, P. A., Sridhar, J., King, L. S. T., Blond, S. Y., Duka, T., Rusnak, M., & Sidhu, A. (2006). Highly potent and specific GSK-3β inhibitors that block tau phosphorylation and decrease α-synuclein protein expression in a cellular model of Parkinson's disease. ChemMedChem, 1(2), 256-266. https://doi.org/10.1002/cmdc.200500039