2. Academic Validation
  3. First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease

First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease

  • ACS Chem Neurosci. 2024 Jun 5;15(11):2099-2111. doi: 10.1021/acschemneuro.4c00061.
Alan Santini 1,  Elisa Tassinari 1,  Eleonora Poeta 2,  Manuela Loi 3,  Elisabetta Ciani 3,  Stefania Trazzi 3,  Rebecca Piccarducci 4,  Simona Daniele 4,  Claudia Martini 4,  Barbara Pagliarani 1,  Andrea Tarozzi 1,  Matteo Bersani 5,  Francesca Spyrakis 5,  Daniela Danková 6,  Christian A Olsen 6,  Roberto Soldati 1,  Vincenzo Tumiatti 1,  Serena Montanari 1,  Angela De Simone 5,  Andrea Milelli 1
Affiliations

Affiliations

  • 1 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Francesco Selmi 3, 40126 Bologna, Italy.
  • 3 Department of Biomedical and Neuromotor Science, Alma Mater Studiorum-University of Bologna, Piazza di Porta S. Donato, 2, 40126 Bologna, Italy.
  • 4 Department of Pharmacy, University of Pisa, Via Bonanno Pisano, 6, 56126 Pisa, Italy.
  • 5 Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Turin, Italy.
  • 6 Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark.
PMID: 38747979 DOI: 10.1021/acschemneuro.4c00061
Abstract

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3β (GSK-3β). The synthesized compounds are highly potent GSK-3β, HDAC2, and HDAC6 inhibitors with IC50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 μM concentration, blocks hyperphosphorylation of Tau Protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.

Keywords

Alzheimer’s disease; Glycogen Synthase Kinase 3β; Histone Deacetylase; Multitarget Drugs; Neuroprotection.

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