Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor That Attenuates Disease Progression in Alzheimer’s Disease Mouse Models
Open accessAbstract
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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p38α MAPK has been shown to mediate Aβ-induced expression of various proinflammatory cytokines/chemokines from microglial cells that causes neuroinflammation.
“First, p38α MAPK has been shown to mediate Aβ-induced expression of various proinflammatory cytokines/chemokines from microglial cells that causes neuroinflammation [25, 26, 29, 35].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [25]
The Methods (Cell Based Activity) and Results and Discussion (Kinome Target Selectivity; page unavailable) show that inhibiting p38αMAPK signaling reduced proinflammatory IL-1β production in LPS-stimulated microglial cells. They do not show Aβ-induced production of various cytokines or chemokines by microglia, or establish that this production causes neuroinflammation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTargeted inactivation of p38α MAPK with small molecule inhibitors prevents the production of proinflammatory cytokines, reduces neurodegeneration, and improves neuronal and cognitive functions in rodent models of amyloid pathology.
“Targeted inactivation of p38α MAPK with small molecule inhibitors prevents the production of proinflammatory cytokines, reduces neurodegeneration, and improves neuronal and cognitive functions in rodent models of amyloid pathology [25, 26, 29, 35].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [25]
In Results and Discussion (page unavailable), the paper reports that MW150 attenuated proinflammatory IL-1β production in cultured microglia and improved memory performance in two amyloid-related mouse models. It does not show that cytokine production was prevented in those mice or that neurodegeneration was reduced; improvement in neuronal function is discussed through earlier work rather than demonstrated here. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe recent description of a drug candidate that retains all of the positive attributes of MW181, but is further optimized for bioavailability and in-vivo safety, provides the means to extend the rationale presented here for tauopathies toward clinical proof of concept.
“The recent description [25] of a drug candidate that retains all of the positive attributes of MW181, but is further optimized for bioavailability and in-vivo safety, provides the means to extend the rationale presented here for tauopathies toward clinical proof of concept.”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [25]
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Experimental — accuracy not yet measuredSignaling through p38 MAPK, especially the p38α isoform, is a critical component for cytokine production in activated microglia.
“Signaling through p38 MAPK, especially the p38α isoform, has also been discovered recently to be a critical component for cytokine production in activated microglia [25, 26].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [25]
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- Authors
- Roy, S. M., Grum-Tokars, V. L., Schavocky, J. P., Saeed, F., Staniszewski, A., Teich, A. F., Arancio, O., Bachstetter, A. D., Webster, S. J., Van Eldik, L. J., Minasov, G., Anderson, W. F., Pelletier, J. C., & Watterson, D. M.
- Affiliations
- Northwestern University (US)
- Columbia University (US)
- University of Kentucky (US)
- University of Kentucky , , ,
- Corresponding author
- Watterson, D. Martin
- ORCID
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-02-13
- Volume
- 6
- Issue
- 4
- Pages
- 666-680
- ISSN
- 1948-7193 (ISSN-L)
- PMC
- PMC4404319
- OpenAlex
- W2074981365
- Cited by
- 99
- References
- 5
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 9 · 2023: 15 · 2022: 2 · 2021: 9 · 2020: 7 · 2019: 9 · 2018: 11 · 2017: 10 · 2016: 9 · 2015: 3
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Chemical Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Columbia Academic Commons (Columbia University)
- Funders
- National Institute on Aging (R01AG031311, U01AG043415)
- National Institute of Neurological Disorders and Stroke (R01NS056051)
- Alzheimer Drug Discovery Foundation (261108)
- Edward N. and Della L. Thome Memorial Foundation (NA)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- p38α MAPK, Alzheimer's disease, stress kinases, synaptic dysfunction, spatial memory, associative memory, CNS drug development, stress behavior
- MeSH terms
- Alzheimer Disease, Animals, Association Learning, Brain, Cell Line, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Male, Memory Disorders, Mice, Transgenic, Microsomes, Liver, Pyridazines, Synapses, Molecular Structure, Rats, Sprague-Dawley, Disease Progression, Neuroprotective Agents, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 14, Spatial Memory
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