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Cited by 81Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingComputational Drug Discovery Methods

Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction

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Watterson, D. Martin, Grum-Tokars, Valerie L., Roy, Saktimayee M., Schavocky, James P., Bradaric, Brinda Desai, Bachstetter, Adam D., Xing, Bin, Dimayuga, Edgardo +8 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0066226PMC PMC3694096
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Abstract

Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will facilitate future kinase inhibitor design. Overall, our studies deliver highly selective in vivo probes appropriate for CNS investigations and demonstrate that modulation of p38αMAPK activity can attenuate synaptic dysfunction.

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Crossref · 10.1371/journal.pone.0066226

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  • MW181 is a highly selective p38α MAPK inhibitor.

    “MW01-10-181SRM (or MW181), a highly selective p38α MAPK inhibitor [26]”

    From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [26]

    The Results section identifies MW181 as a p38αMAPK inhibitor, but describes it as a p38MAPK subfamily inhibitor rather than an isoform-selective one. Kinase profiling found similar inhibitory affinities for p38αMAPK, p38βMAPK, and NLK; the paper identifies MW108, not MW181, as more selective for p38αMAPK. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • 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 [26]

    The Results section on CNS mechanism of action links microglial p38αMAPK to increased proinflammatory cytokine production, but the experiments described there use LPS or TLR ligands and measure IL-1β. The Results section on amyloid-beta elevation reports rescue of Aβ-induced synaptic deficits, not Aβ-induced microglial expression of various cytokines or chemokines. The References identify a separate study on Aβ-induced microglial cytokine up-regulation; this paper does not itself establish the full claim. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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.

    “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 [26]

    The Results sections on in vivo efficacy and CNS mechanism (page numbers unavailable) report that p38α MAPK inhibitors rescued amyloid-β-induced synaptic and memory deficits in mice and suppressed stressor-induced IL-1β increases. They do not show reduced neurodegeneration, and the cytokine experiments used LPS or other TLR stimuli rather than an amyloid-pathology model; suppression of elevated IL-1β is also narrower than preventing cytokine production. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Signaling 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 [26]

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Research works printed but not linked: 1

  1. [50]Pettus LH, Wurz RP, Xu B, Herberich B, Henkle Q, et al (2010) Discovery and evaluation of 7-Alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38α mitogen-activated protein kinase. J Med Chem 53: 2973– 2985. 20218619

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Authors
Watterson, D. M., Grum-Tokars, V. L., Roy, S. M., Schavocky, J. P., Bradaric, B. D., Bachstetter, A. D., Xing, B., Dimayuga, E., Saeed, F., Zhang, H., Staniszewski, A., Pelletier, J. C., Minasov, G., Anderson, W. F., Arancio, O., & Van Eldik, L. J.
Affiliations
  • Northwestern University (US)
  • University of Kentucky (US)
  • Columbia University (US)
Corresponding author
Watterson, D. Martin
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-06-26
Volume
8
Issue
6
Pages
e66226
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0066226
PMC
PMC3694096
OpenAlex
W2071201894
Cited by
80
References
51
Citations by year
2026: 7 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 9 · 2017: 7 · 2016: 7 · 2015: 6 · 2014: 5 · 2013: 1
FWCI
4.41
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Columbia Academic Commons (Columbia University)
Funders
  • Alzheimer's Association
  • Edward N. and Della L. Thome Memorial Foundation
  • National Institutes of Health
  • National Institute on Aging (U01AG043415, R01AG031311, F32AG037280)
  • National Institute of Neurological Disorders and Stroke (R01NS056051, R01NS064247, R01NS047586)
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
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
p38α MAPK, kinase inhibitors, synaptic dysfunction, amyloid-beta, Alzheimer's disease, pharmacoinformatics, target engagement, disease-modifying therapy, neurodegeneration
MeSH terms
Animals, Brain, Cell Line, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Peptide Fragments, Pyridazines, Pyridines, Drug Design, Amyloid beta-Peptides, Long-Term Potentiation, Catalytic Domain, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 14

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