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

Demuro, Stefania; Sauvey, Conall; Tripathi, Shailesh; Martino, Rita Maria Concetta Di; Shi, Da; Ortega, J.A.; Russo, Debora; Balboni, Beatrice; Giabbai, Barbara; Storici, Paola; Girotto, Stefania; Abagyan, Ruben; Cavalli, Andrea

doi:10.1016/j.ejmech.2021.114054

Cited by 13 publications

(10 citation statements)

References 50 publications

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“…ARN25068 was described as a triple inhibitor of GSK-3β, FYN, and DYRK1A (IC 50 = 4.2, 2.2, and 903 nM, respectively). 106 ARN25068 was cocrystallized with DYRK1A (PDB: 7OY6). We found that it was a potent inhibitor of CLK1, CLK2, CLK4, and GSK3 (IC 50 values: 76, 83, 51, 35 nM, respectively), but a poor inhibitor of DYRKs (IC 50 = 1−10 μM).…”

Section: ■ Resultsmentioning

confidence: 99%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

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Section: ■ Resultsmentioning

confidence: 99%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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“…[19,20] There is a need for more potent new products. [58] We observed that obacunone (5) and gedunin (4) can form equally stable complexes with GSK-3β, with ΔE values in the range −57 to −60 kcal/mol, that is, about 20% less than the values calculated with the two references (Table 1). Typical models of obacunone (5) and gedunin (4) bound to GSK-3β are presented in Figure 3.…”

Section: In Silico Molecular Docking Proceduresmentioning

confidence: 57%

Molecular docking study of GSK‐3β interaction with nomilin, kihadanin B, and related limonoids and triterpenes with a furyl‐δ‐lactone core

Vergoten

Bailly

2022

J Biochem & Molecular Tox

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Glycogen synthase kinase‐3β (GSK‐3β) is a target enzyme considered for the treatment of multiple human diseases, from neurodegenerative pathologies to viral infections and cancers. Numerous inhibitors of GSK‐3β have been discovered but thus far only a few have reached clinical trials and only one drug, tideglusib (1), has been registered. Natural products targeting GSK‐3β have been identified, including the two anticancer limonoids obacunone (5) and gedunin (4), both presenting a furyl‐δ‐lactone core. To help identifying novel GSK‐3β ligands, we have performed a molecular docking study with 15 complementary natural products bearing a furyl‐δ‐lactone unit (such as limonin (6) and kihadanins A (8) and B (9)) or a closely related structure (such as cedrelone (10) and nimbolide (11)). The formation of GSK‐3β‐binding complexes for those natural products was compared to reference GSK‐3β ATP‐competitive inhibitors LY2090314 (3) and AR‐A014418 (2). Our in silico analysis led to the identification of two new GSK‐3β‐binding natural products: kihadanin B (9) and nomilin (7). The latter surpassed the reference compounds in terms of calculated empirical energy of interaction (ΔE). Nomilin (7) can possibly bind to the active site of GSK‐3β, notably via the furyl‐δ‐lactone core and its 1‐acetyl group, implicated in the protein interaction. Compound structure‐binding relationships are discussed. The study should help the discovery of novel natural products targeting GSK‐3β.

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“…Numerous studies have supported that DYRK inhibition either rescues, prevents, or reverses Alzheimer's Disease pathologyboth histological and behavioralin models of the disease (78)(79)(80)(81)(82). Approaches to inhibit DYRK have been both genetic (81) and pharmacologic (83)(84)(85)(86)(87). Though there is an abundance of literature on DYRK and tau phosphorylation and amyloid pathology, the pathologic mechanism by which it functions remains unclear.…”

Section: The Underrepresented Kinasesmentioning

confidence: 99%

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Henkel

Joyce

Shedroff

et al. 2022

Preprint

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Neurons and astrocytes derived from Alzheimers Disease (AD) patient induced pluripotent stem cells are an evolving technology used to study the pathogenesis and etiology of AD. As the utility of mouse models of AD are increasingly coming into questions, using iPSC technology may offer an opportunity to study this disease with human substrates. Herein, we using a hypothesis generating platform, the PamGene12 Kinome Array, to identify core protein kinases in neurons and astrocytes derived from familial AD patient iPSCs. We identified five core protein kinases in these cells and examined the pathways in which they are enriched. Importantly, we complement our findings using an in-silico approach with postmortem AD brain datasets. While these protein kinases have been conceptualized in the context of traditional AD pathology, they have not been explored in the context of aberrant signaling in the pathophysiology of the disease.

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

Cited by 13 publications

References 50 publications

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Molecular docking study of GSK‐3β interaction with nomilin, kihadanin B, and related limonoids and triterpenes with a furyl‐δ‐lactone core

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

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