scholarly journals From kinase inhibitors to multitarget ligands as powerful drug leads for Alzheimer’s disease using protein‐templated synthesis

2021 ◽  
Author(s):  
Ana Martinez Gil ◽  
Vanesa Nozal ◽  
Alfonso Garcia-Rubia ◽  
Eva P Cuevas ◽  
Concepcion Perez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Kinase Inhibitors ◽  
Templated Synthesis ◽  
Drug Leads

scholarly journals “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yuxing Xia ◽  
Stefan Prokop ◽  
Benoit I. Giasson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Kinase Inhibitors ◽  
Tau Phosphorylation ◽  
Phosphorylated Tau ◽  
Clinical Biomarkers ◽  
Early Results ◽  
Recent Developments ◽  
Tau Aggregation

AbstractPhosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau  could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

scholarly journals Kororamides, Convolutamines, and Indole Derivatives as Possible Tau and Dual-Specificity Kinase Inhibitors for Alzheimer’s Disease: A Computational Study

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 386 ◽  
Author(s):  
Laura Llorach-Pares ◽  
Alfons Nonell-Canals ◽  
Conxita Avila ◽  
Melchor Sanchez-Martinez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Kinase Inhibitors ◽  
Computational Study ◽  
Therapeutic Application ◽  
Ongoing Research ◽  
Casein Kinase 1 ◽  
Dual Specificity ◽  
Potential Therapeutic Application

Alzheimer’s disease (AD) is becoming one of the most disturbing health and socioeconomic problems nowadays, as it is a neurodegenerative pathology with no treatment, which is expected to grow further due to population ageing. Actual treatments for AD produce only a modest amelioration of symptoms, although there is a constant ongoing research of new therapeutic strategies oriented to improve the amelioration of the symptoms, and even to completely cure the disease. A principal feature of AD is the presence of neurofibrillary tangles (NFT) induced by the aberrant phosphorylation of the microtubule-associated protein tau in the brains of affected individuals. Glycogen synthetase kinase-3 beta (GSK3β), casein kinase 1 delta (CK1δ), dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) and dual-specificity kinase cdc2-like kinase 1 (CLK1) have been identified as the principal proteins involved in this process. Due to this, the inhibition of these kinases has been proposed as a plausible therapeutic strategy to fight AD. In this study, we tested in silico the inhibitory activity of different marine natural compounds, as well as newly-designed molecules from some of them, over the mentioned protein kinases, finding some new possible inhibitors with potential therapeutic application.

scholarly journals P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

2020 ◽  
Vol 21 (15) ◽  
pp. 5485
Author(s):  
Ursula A. Germann ◽  
John J. Alam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Therapeutic Target ◽  
Kinase Inhibitors ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Effects ◽  
P38α Kinase

Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

Plant alkaloids as drug leads for Alzheimer's disease

2015 ◽  
Vol 89 ◽  
pp. 260-270 ◽  
Author(s):  
Yu Pong Ng ◽  
Terry Cho Tsun Or ◽  
Nancy Y. Ip
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plant Alkaloids ◽  
Drug Leads

scholarly journals Effects of Specific Inhibitors for CaMK1D on a Primary Neuron Model for Alzheimer’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7669
Author(s):  
Paige Grant ◽  
Jitendra Kumar ◽  
Satyabrata Kar ◽  
Michael Overduin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Cortical Neurons ◽  
Kinase Inhibitors ◽  
Tau Hyperphosphorylation ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
Molecular Components ◽  
Specific Inhibitors

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aβ) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aβ-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aβ induced tau hyperphosphorylation in culture, but were not able to protect cells from Aβ induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD.

Repurposing of Kinase Inhibitors to Target c-Abl as Potential Therapeutics for Alzheimer’s Disease

2014 ◽  
Vol 9 (4) ◽  
pp. 331-340 ◽  
Author(s):  
Qingzhang Zhu ◽  
Jianchun Chen ◽  
Xi Wu ◽  
Xiaoping Jin ◽  
Bing Ruan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Kinase Inhibitors ◽  
Potential Therapeutics

Identifying GSK-3β kinase inhibitors of Alzheimer's disease: Virtual screening, enzyme, and cell assays

2016 ◽  
Vol 89 ◽  
pp. 11-19 ◽  
Author(s):  
Chih-Hsin Lin ◽  
Yu-Shao Hsieh ◽  
Yih-Ru Wu ◽  
Chia-Jen Hsu ◽  
Hsuan-Chiang Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Kinase Inhibitors ◽  
Cell Assays ◽  
Gsk 3Β

The outcomes of small-molecule kinase inhibitors and the role of ROCK2 as a molecular target for the treatment of Alzheimer's disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Heber Victor Tolomeu ◽  
Carlos Alberto Manssour Fraga
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Active Site ◽  
Rational Design ◽  
Kinase Inhibitors ◽  
Structural Characteristics ◽  
Structural Features ◽  
Relationship Analysis ◽  
Promising Target

Background: Alzheimer's disease is rapidly becoming a major threat to public health, with an increasing number of individuals affected as the world's population ages. In this sense, studies have been carried out aiming at the identification of new small-molecule kinase inhibitors useful for the treatment of Alzheimer's disease. Objective: In the present study, we investigated the compounds developed as inhibitors of different protein kinases associated with the pathogenesis of Alzheimer's disease. Methods: The applied methodology was the use of the Clarivate Analytics Integrity and ClinicalTrials.com databases. Moreover, we highlight ROCK2 as a promising target despite being little studied for this purpose. A careful structure-activity relationship analysis of the ROCK2 inhibitors was performed to identify important structural features and fragments for the interaction with the kinase active site, aiming to rationally design novel potent and selective inhibitors. Results: We were able to notice some structural characteristics that could serve as the basis to better guide the rational design of new ROCK2 inhibitors as well as some more in-depth characteristics regarding the topology of the active site of both isoforms of these enzymes, thereby identifying differences that could lead to planning more selective compounds. Conclusion: We hope that this work can be useful to update researchers working in this area, enabling the emergence of new ideas and a greater direction of efforts for designing new ROCK2 inhibitors to identify new therapeutic alternatives for Alzheimer's disease.

Fungal Metabolites as Promising New Drug Leads for the Treatment of Alzheimer's Disease

2019 ◽  
pp. 1-39 ◽  
Author(s):  
Jacqueline Aparecida Takahashi ◽  
Denise Sande ◽  
Gesiane da Silva Lima ◽  
Marília Aparecida Fidelis e Moura ◽  
Matheus Thomaz Nogueira Silva Lima
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fungal Metabolites ◽  
New Drug ◽  
Drug Leads
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