Abstract
So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3β, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.
Keywords: Multitargeted approach, substituent effects, kinase inhibition, tau protein, enzyme binding, total tau.
Current Alzheimer Research
Title:Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach
Volume: 13 Issue: 12
Author(s): V. Tell, I. Hilbrich, M. Holzer, Frank Totzke, Christoph Schachtele, Inna Slynko, Wolfgang Sippl and A. Hilgeroth
Affiliation:
Keywords: Multitargeted approach, substituent effects, kinase inhibition, tau protein, enzyme binding, total tau.
Abstract: So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3β, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.
Export Options
About this article
Cite this article as:
Tell V., Hilbrich I., Holzer M., Totzke Frank, Schachtele Christoph, Slynko Inna, Sippl Wolfgang and Hilgeroth A., Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach, Current Alzheimer Research 2016; 13 (12) . https://dx.doi.org/10.2174/1567205013666160615091821
DOI https://dx.doi.org/10.2174/1567205013666160615091821 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Nonconvulsive (Dialeptic) Status Epilepticus in Children
Current Pediatric Reviews In Silico Dynamic Molecular Interaction Networks for the Discovery of New Therapeutic Targets
Current Pharmaceutical Design The Molecular Pathology of Huntingtons Disease (HD)
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Neurotransmitter Regulation of Adult Neurogenesis: Putative Therapeutic Targets
CNS & Neurological Disorders - Drug Targets Functional Neurochemistry of Alzheimers Disease
Current Pharmaceutical Design Metabolic Programming Nowadays (or Perhaps Now and then?)
Current Nutrition & Food Science Identification of Inflammatory, Metabolic, and Cell Survival Pathways Contributing to Cerebral Small Vessel Disease by Postmortem Gene Expression Microarray
Current Neurovascular Research The Role of Oxidative Stress in Huntington’s Disease: Are Antioxidants Good Therapeutic Candidates?
Current Drug Targets Medicinal Agents and Metabolic Syndrome
Current Medicinal Chemistry Patent Selections
Recent Patents on CNS Drug Discovery (Discontinued) Topical Discoveries on Multi-Target Approach to Manage Alzheimer’s Disease
Current Drug Metabolism MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders
Current Genomics Genetic Risk Factors for Depression in Alzheimer´s Disease Patients
Current Alzheimer Research Structural and Functional MRI in Mild Cognitive Impairment
Current Alzheimer Research Dual Effects of Antioxidants in Neurodegeneration: Direct Neuroprotection against Oxidative Stress and Indirect Protection via Suppression of Gliamediated Inflammation
Current Pharmaceutical Design Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer’s Disease
Current Alzheimer Research Peripheral Mononuclear Cell Rejuvenation for Senescence Surveillance in Alzheimer Disease
Current Pharmaceutical Design Subjective Spatial Navigation Complaints - A Frequent Symptom Reported by Patients with Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease
Current Alzheimer Research Multifunctional Tacrine Derivatives in Alzheimer’s Disease
Current Topics in Medicinal Chemistry Noradrenergic System in Down Syndrome and Alzheimer’s Disease A Target for Therapy
Current Alzheimer Research