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

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-06-10 DOI:10.1016/j.ejmech.2025.117838

Alan Santini , Elisa Tassinari , Alessandra Altomare , Manuela Loi , Elisabetta Ciani , Stefania Trazzi , Rebecca Piccarducci , Simona Daniele , Claudia Martini , Barbara Pagliarani , Andrea Tarozzi , Matteo Bersani , Francesca Spyrakis , Daniela Danková , Eleonora Poeta , Simone Raimondi , Lara Davani , Giancarlo Aldini , Vincenza Andrisano , Angela De Simone , Andrea Milelli

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引用次数: 0

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.

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基于ar - a014418的双糖原合成酶激酶3β /组蛋白去乙酰化酶抑制剂作为阿尔茨海默病的潜在治疗药物

阿尔茨海默病（AD）是最常见的痴呆症类型，目前在世界范围内是一个未满足的医疗需求。它被认为是多个生理网络系统崩溃的结果，可以通过旨在恢复受干扰网络的多靶点药物（MTDs）充分解决。越来越多的证据表明糖原合成酶激酶3β (GSK-3β)和组蛋白去乙酰化酶（hdac）协同参与疾病的发病机制。为了继续开发针对AD的MTDs，我们操纵了先前报道的GSK-3β抑制剂AR-A014418的结构，以开发一类新的GSK-3β/ hdac双结合剂。在所合成的34个衍生物中，化合物19对GSK-3β （IC50 = 0.04±0.01 μM）、HDAC2 （IC50 = 1.05±0.11 μM）和HDAC6 （IC50 = 1.52±0.06 μM）均有抑制作用。此外，化合物19抑制细胞中HDAC2和6的活性，阻断tau蛋白的过度磷酸化。有趣的是，它对SH-SY5Y细胞在100 μM范围内无毒，并具有神经保护作用。此外，为了更好地阐明化合物19的作用方式，我们利用蛋白质组分析研究了其对SH-SY5Y细胞分子通路的影响。我们发现了化合物19的潜力，它代表了开发创新疾病调节剂的一个有希望的打击。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.