Dataset Information

ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders.

ABSTRACT: The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3β and FYN inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau hyperphosphorylation.

SUBMITTER: Demuro S

PROVIDER: S-EPMC9704499 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders.

Demuro Stefania S Sauvey Conall C Tripathi Shailesh K SK Di Martino Rita M C RMC Shi Da D Ortega Jose A JA Russo Debora D Balboni Beatrice B Giabbai Barbara B Storici Paola P Girotto Stefania S Abagyan Ruben R Cavalli Andrea A

European journal of medicinal chemistry 20211216

The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence h ...[more]

PMID: 34959172

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Project description:Increasing evidence is suggesting that amyloid-β peptide (Aβ), a characteristic of Alzheimer's disease (AD), induces oxidative stress and mitochondrial dysfunction, leading to neuronal death. This study aimed to demonstrate the antioxidant and anti-apoptotic effects of fucoxanthin, a major marine carotenoid found in brown algae, against neuronal injury caused by Aβ. Non-toxic dose range of fucoxanthin (0.1-5 µM) were selected for the neuroprotective study against Aβ25-35. The PC12 cells were pretreated with different concentrations of fucoxanthin for 1 h before being exposed to 10 µM Aβ25-35 for another 24 h. The present results showed that fucoxanthin inhibited Aβ25-35-induced cell death by recovering cell cycle arrest and decreasing intracellular reactive oxygen species (ROS) level. The compound enhanced mitochondrial recovery and regulated apoptosis related proteins including B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) from Aβ25-35-induced oxidative stress. Concomitantly, fucoxanthin increased the expression of nuclear factor E2-related factor 2 (Nrf2) and its downstream phase II detoxifying enzymes including NADPH: quinone oxidoreductase-1 (NQO-1), glutamate cysteine ligase modifier subunit (GCLm), and thioredoxin reductase 1 (TrxR1), whereas it decreased the expression of cytoplasmic Kelch-like ECH-associated protein 1 (Keap1). Moreover, pretreatment of fucoxanthin reduced Fyn phosphorylation via protein kinase B (Akt)-mediated inhibition of glycogen synthase kinase-3β (GSK-3β), which increased the nuclear localization of Nrf2, suggesting that the compound enhanced Nrf2 expression by the activation of upstream kinase as well as the dissociation of the Nrf2-Keap1 complex. Further validation with a specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 demonstrated that the fucoxanthin-mediated Nrf2 antioxidant defense system was directly associated with the Akt/GSK-3β/Fyn signaling pathway. In silico simulation revealed that the oxygen groups of fucoxanthin participated in potent interactions with target markers in the Nrf2 signaling pathway, which may affect the biological activity of target markers. Taken together, the present results demonstrated that the preventive role of fucoxanthin on Aβ-stimulated oxidative injury and apoptosis via Akt/GSK-3β/Fyn signaling pathway. This study would provide a useful approach for potential intervention for AD prevention.

Dataset Information

ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders.

Publications

ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders.

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