Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent to Combat Alzheimer's Disease

Angela De Simone, Valeria La Pietra, Nibal Betari, Nicola Petragnani, Mariarosaria Conte, Simona Daniele, Deborah Pietrobono, Claudia Martini, Sabrina Petralla, Raffaella Casadei, Lara Davani, Flavia Frabetti, Pasquale Russomanno, Ettore Novellino, Serena Montanari, Vincenzo Tumiatti, Patrizia Ballerini, Federica Sarno, Angela Nebbioso, Lucia AltucciBarbara Monti, Vincenza Andrisano, Andrea Milelli

Research output: Contribution to journalArticle

Abstract

Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound 11 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against H2O2 and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound 11 shows no lethality in a wt-zebrafish model (<100 μM) and high water solubility.

Original languageEnglish
Pages (from-to)469-474
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 11 2019

Keywords

  • dual binding agents
  • epigenetics
  • glycogen synthase kinase 3β
  • histone deacetylases
  • neuroprotection
  • Polypharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    De Simone, A., La Pietra, V., Betari, N., Petragnani, N., Conte, M., Daniele, S., Pietrobono, D., Martini, C., Petralla, S., Casadei, R., Davani, L., Frabetti, F., Russomanno, P., Novellino, E., Montanari, S., Tumiatti, V., Ballerini, P., Sarno, F., Nebbioso, A., ... Milelli, A. (2019). Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent to Combat Alzheimer's Disease. ACS Medicinal Chemistry Letters, 10(4), 469-474. https://doi.org/10.1021/acsmedchemlett.8b00507