ArticleACS chemical neuroscience2015
Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.
Article in ACS chemical neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 97 citations in OpenAlex.
- A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease.Alzheimer's research & therapy · 2021Trial
- Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction.Journal of medicinal chemistry · 2026Article
- Specific inhibition of p38α MAPK dampens neuroinflammation during acute alcohol withdrawal in mouse BV2 microglial cell line and rat organotypic hippocampal slice cultures.Alcohol (Fayetteville, N.Y.) · 2026Article
- Roles of MAPKs, Including Those Activated by BDNF/TrkB, and Their Contribution in Neurodegenerative Diseases.International journal of molecular sciences · 2026Review
- Computational Discovery and Optimization of a Potent, Selective, and Drug-Like Scaffold for p38α Inhibition.Drug design, development and therapy · 2026Article
- Alcohol addiction and Alzheimer's disease: a molecular collision course.Translational psychiatry · 2025Review
- Multiple sclerosis as a genetic risk factor for Alzheimer's disease: Insights from Mendelian randomisation.Neurodegenerative disease management · 2025Article
- Identification of p38 MAPK inhibition as a neuroprotective strategy for combinatorial SMA therapy.EMBO molecular medicine · 2025Article
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer's Disease.Cells · 2025Review
- Endosomal traffic disorders: a driving force behind neurodegenerative diseases.Translational neurodegeneration · 2024Review
- Therapeutic targeting of senescent cells in the CNS.Nature reviews. Drug discovery · 2024Review
- A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies.Brain, behavior, & immunity - health · 2024Article
- p38α Mitogen-Activated Protein Kinase-An Emerging Drug Target for the Treatment of Alzheimer's Disease.Molecules (Basel, Switzerland) · 2024Review
- CNS-Active p38α MAPK Inhibitors for the Management of Neuroinflammatory Diseases: Medicinal Chemical Properties and Therapeutic Capabilities.Molecular neurobiology · 2024Review
- Visible Light-Promoted Regioselective Benzannulation of Vinyl Sulfoxonium Ylides with Ynoates.JACS Au · 2024Article
- The P38MAPK/ATF2 signaling pathway is involved in PND in mice.Experimental brain research · 2024Article
- Common cytokine receptor gamma chain family cytokines activate MAPK, PI3K, and JAK/STAT pathways in microglia to influence Alzheimer's Disease.Frontiers in molecular neuroscience · 2024Article
- Pyrrolo[2,3-D]Pyrimidines as EGFR and VEGFR Kinase Inhibitors: A Comprehensive SAR Review.Current medicinal chemistry · 2024Review
- Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease.Pharmaceutics · 2023Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150's exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.