PUBLICATION
Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer's Disease
- Authors
- 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., Altucci, L., Monti, B., Andrisano, V., Milelli, A.
- ID
- ZDB-PUB-190422-4
- Date
- 2019
- Source
- ACS Medicinal Chemistry Letters 10: 469-474 (Journal)
- Registered Authors
- Casadei, Raffaella, Frabetti, Flavia
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 30996781 Full text @ ACS Med. Chem. Lett.
Citation
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., Altucci, L., Monti, B., Andrisano, V., 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. 10:469-474.
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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-171 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping