2. Academic Validation
  3. AR-A014418-based dual Glycogen Synthase Kinase 3β/Histone Deacetylase inhibitors as potential therapeutics for Alzheimer's disease

AR-A014418-based dual Glycogen Synthase Kinase 3β/Histone Deacetylase inhibitors as potential therapeutics for Alzheimer's disease

  • Eur J Med Chem. 2025 Jun 10:296:117838. doi: 10.1016/j.ejmech.2025.117838.
Alan Santini 1,  Elisa Tassinari 1,  Alessandra Altomare 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,  Eleonora Poeta 7,  Simone Raimondi 1,  Lara Davani 2,  Giancarlo Aldini 2,  Vincenza Andrisano 1,  Angela De Simone 5,  Andrea Milelli 8
Affiliations

Affiliations

  • 1 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
  • 2 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133, Milan, Italy.
  • 3 Department of Biomedical and Neuromotor Sciences, 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.
  • 7 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy.
  • 8 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy. Electronic address: andrea.milelli3@unibo.it.
PMID: 40517573 DOI: 10.1016/j.ejmech.2025.117838
Abstract

Alzheimer's disease (AD), the most common type of dementia, currently represents an unmet medical need worldwide. It is considered the result of a systemic breakdown of multiple physiological networks which might be adequately tackled by multitarget drugs (MTDs) aimed at restoring the perturbed networks. Accumulating evidence suggests that Glycogen Synthase Kinase 3β (GSK-3β) and Histone Deacetylases (HDACs) synergistically contribute to disease pathogenesis. In a continuation of our efforts to develop MTDs for AD, we manipulated the structure of a previously reported GSK-3β Inhibitor, AR-A014418, to develop a new class of dual GSK-3β/HDACs binding agents. Among the 34 synthesized derivatives, compound 19 showed encouraging results, inhibiting GSK-3β (IC50 = 0.04 ± 0.01 μM) HDAC2 (IC50 = 1.05 ± 0.11 μM), and HDAC6 (IC50 = 1.52 ± 0.06 μM). In addition, compound 19 inhibits HDAC2 and 6 activities in cells and blocks tau hyperphosphorylation. Interestingly, it is nontoxic in SH-SY5Y cells up to 100 μM, and exerts neuroprotective effects. Moreover, to better elucidate the mode of action of compound 19, its effects on the molecular pathways of SH-SY5Y cells were studied using a proteome-wide analysis. We uncovered the potential of compound 19, which represents a promising hit for the development of innovative disease-modifying agents.

Keywords

Alzheimer's disease; Glycogen Synthase kinase 3β; Histone Deacetylases; Neuroprotection; Tau.

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