Anti-Alzheimer effects of an HDAC6 inhibitor, WY118, alone and in combination of lithium chloride: Synergistic suppression of ferroptosis via the modulation of tau phosphorylation and MAPK signaling

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177605 - 177605

Published: April 1, 2025

Language: Английский

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Identification of novel ligands against GSK-3β: Molecular Docking, ADMET filtering, MD Simulations, MM-GBSA studies, and DFT analysis

Computational Biology and Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108478 - 108478

Published: April 1, 2025

Language: Английский

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Protein Kinases – High Yield Targets for Cancer and Dementia Drug Discovery

The American Journal of Medicine, Journal Year: 2024, Volume and Issue: 137(11), P. 1055 - 1058

Published: June 24, 2024

Language: Английский

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Synthesis of novel hybrids of 1,2,3-triazoles-hydrazone: targeting cholinesterases and Alzheimer's related genes

Future Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 16(15), P. 1519 - 1535

Published: June 12, 2024

Aim: A new series of 1,2,3-triazole-hydrazone derivatives were developed to evaluate their anti-Alzheimer's activity. Materials & methods: All compounds screened toward cholinesterases via the modified Ellman's method. The toxicity assay on SH-SY5Y cells was performed using MTT assay, and expression levels GSK-3α, GSK-3β, DYRK1 CDK5 assessed in presence 6m 6p. Results: 6p; acting as mixed-type inhibitors, exhibited promising acetylcholinesterase butyrylcholinesterase inhibitory activity, respectively. demonstrated no under tested concentrations positively impacted neurodegenerative pathways. Notably, displayed a significant downregulation mRNA GSK-3β CDK5. Conclusion: target could be considered developing disease agents.

Language: Английский

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Update on JNK inhibitor patents: 2015 to present

Expert Opinion on Therapeutic Patents, Journal Year: 2024, Volume and Issue: 34(10), P. 907 - 927

Published: Sept. 3, 2024

c-Jun N-terminal kinase (JNK) regulates various biological processes through the phosphorylation cascade and is closely associated with numerous diseases, including inflammation, cardiovascular neurological disorders. Therefore, JNKs have emerged as potential targets for disease treatment.

Language: Английский

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Identification of AS1842856 as a novel small‐molecule GSK3α/β inhibitor against Tauopathy by accelerating GSK3α/β exocytosis

Aging Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 17, 2024

Abstract Glycogen synthase kinase‐3α/β (GSK3α/β) is a critical kinase for Tau hyperphosphorylation which contributes to neurodegeneration. Despite the termination of clinical trials GSK3α/β inhibitors in Alzheimer's disease (AD) treatment, there pressing need novel therapeutic strategies targeting GSK3α/β. Here, we identified compound AS1842856 (AS), specific forkhead box protein O1 (FOXO1) inhibitor, reduced intracellular content FOXO1‐independent manner. Specifically, AS directly bound GSK3α/β, promoting its translocation multivesicular bodies (MVBs) and accelerating exocytosis, ultimately decreasing content. Expectedly, treatment effectively suppressed cells exposed okadaic acid or expressing P301S mutant. Furthermore, was visualized penetrate blood–brain barrier (BBB) using an imaging mass microscope. Long‐term enhanced cognitive function transgenic mice by mitigating through downregulation expression brain. Altogether, represents small‐molecule inhibitor that facilitates holding promise as agent hyperactivation‐associated disorders.

Language: Английский

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Leucettinib-21, a DYRK1A Kinase Inhibitor as Clinical Drug Candidate for Alzheimer’s Disease and Down Syndrome

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 101(s1), P. S95 - S113

Published: Oct. 18, 2024

Alzheimer's disease (AD) and Down syndrome (DS) share a common therapeutic target, the dual-specificity, tyrosine phosphorylation activated kinase 1A (DYRK1A). Abnormally active DYRK1A is responsible for cognitive disorders (memory, learning, spatial localization) observed in both conditions. In DS, overexpressed due to presence of gene on chromosome 21. AD, calcium-activated calpains cleave full-length (FL-DYRK1A) into more stable active, low molecular weight, (LMW-DYRK1A). Genetic pharmacological experiments carried out with animal models AD DS strongly support idea that inhibitors might be able correct memory/learning people DS. Starting from marine sponge natural product, Leucettamine B, Perha Pharmaceuticals has optimized, through classical medicinal chemistry, extensively characterized small molecule drug candidate, Leucettinib-21. Regulatory preclinical safety studies rats minipigs have been completed formulation Leucettinib-21 optimized as immediate-release tablets. now undergoing phase 1 clinical trial (120 participants, including 12 adults patients AD). The potential presented.

Language: Английский

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Palmitoyl-L-carnitine induces tau phosphorylation and mitochondrial dysfunction in neuronal cells

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(11), P. e0313507 - e0313507

Published: Nov. 13, 2024

Alzheimer’s disease (AD) is characterized by cognitive decline and memory loss, involving mechanisms such as tau hyperphosphorylation mitochondrial dysfunction. Increasing evidence suggests that age-related alterations in metabolite levels are crucial for the pathogenesis of AD. Here, we analyzed serum metabolites from mice various ages (2, 4, 14, 21 months old) using mass spectrometry. We identified palmitoyl-L-carnitine a key with significantly increased aged mice. In vitro experiments SH-SY5Y neuronal cells demonstrated treatment enhanced phosphorylation, fission, elevated intracellular calcium levels. Furthermore, phosphorylation were reduced inhibition GSK-3β, CDK5, calpain, indicating kinases activated overload directly involved increase phosphorylation. Considering fission related to dysfunction, propose level during aging contributes AD pathology through these pathways. These findings highlight significant role lipid metabolism neurodegeneration offer potential therapeutic targets diseases, including

Language: Английский

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Comprehensive safety evaluation of a novel multitargeting compound XYY-CP1106: A candidate for Alzheimer's disease

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116786 - 116786

Published: May 27, 2024

Multitargeting has become a promising strategy for the development of anti-Alzheimer's disease (AD) drugs, considering complexity molecular mechanisms in AD pathology. In most pre-clinical studies, effectiveness these multi-targeted anti-AD drugs been demonstrated but comprehensive safety assessments are lacking. Here, evaluation novel candidate (XYY-CP1106), characterized by its dual-property iron chelation and monoamine oxidase B inhibition, was conducted multifaceted analysis. Acute toxicity mice to investigate oral administration maximum tolerated dose agent. vitro Ames analysis, CHL chromosomal aberration bone marrow micronucleus analysis were executed evaluate genotoxicity. A teratogenesis investigation pregnant meticulously performed XYY-CP1106. Furthermore, 90-day long-term rats investigated cumulative after administration. Strikingly, no toxic phenomena found all investigations, demonstrating relatively high profile compound. The securing heightened translational significance XYY-CP1106 as candidate, supporting rationality multitargeting designs smart drugs.

Language: Английский

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Homoplantaginin Antagonizes N-Methyl-d-aspartate Receptor and Extracellular Signal-Regulated Kinase Signaling in Aβ Oligomers-Induced Neuropathology/Toxicity

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

Extracts from plants/herbals are great resources of drugs and nutrients. Baicalein, a component present in

Language: Английский

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