Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer’s Disease
| Autor: | Deborah Pietrobono, Nicola Petragnani, Vincenza Andrisano, Claudia Martini, Vincenzo Tumiatti, Nibal Betari, Serena Montanari, Simona Daniele, Lara Davani, Angela Nebbioso, Ettore Novellino, F. Frabetti, Barbara Monti, Pasquale Russomanno, Angela De Simone, Andrea Milelli, Federica Sarno, Lucia Altucci, Patrizia Ballerini, Raffaella Casadei, Valeria La Pietra, Mariarosaria Conte, Sabrina Petralla |
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| Přispěvatelé: | De Simone, Angela, La Pietra, Valeria, Betari, Nibal, Petragnani, Nicola, Conte, Mariarosaria, Daniele, Simona, Pietrobono, Deborah, Martini, Claudia, Petralla, Sabrina, Casadei, Raffaella, Davani, Lara, Frabetti, Flavia, Russomanno, Pasquale, Novellino, Ettore, Montanari, Serena, Tumiatti, Vincenzo, Ballerini, Patrizia, Sarno, Federica, Nebbioso, Angela, Altucci, Lucia, Monti, Barbara, Andrisano, Vincenza, Milelli, Andrea, 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., De Simone, A., La Pietra, V., Betari, N., Petragnani, N., Conte, M., Daniele, S., Pietrobono, D., Martini, C., Petralla, S., Casadei, R., D'Avani, Paolo, Frabetti, F., Novellino, E., Montanari, S., Tumiatti, V., Ballerini, P., Sarno, F., Nebbioso, A., Altucci, L., Monti, B., Andrisano, ANGELA-MARIA, Milelli, A. |
| Rok vydání: | 2019 |
| Předmět: |
dual binding agents
Polypharmacology epigenetics dual binding agents glycogen synthase kinase 3β histone deacetylases neuroprotection Polypharmacology Disease 01 natural sciences Biochemistry Neuroprotection GSK-3 Drug Discovery Epigenetics epigenetics glycogen synthase kinase 3β histone deacetylases neuroprotection biology 010405 organic chemistry Chemistry Drug Discovery3003 Pharmaceutical Science Organic Chemistry Neurogenesis 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry Histone Cell culture Acetylation dual binding agent histone deacetylase biology.protein epigenetic |
| Zdroj: | ACS Medicinal Chemistry Letters. 10:469-474 |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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 H(2)O(2) 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 ( |
| Databáze: | OpenAIRE |
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