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
  • 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: [email protected].
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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