Powered by OpenAIRE graph
Found an issue? Give us feedback
image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Europe PubMed Centra...arrow_drop_down
image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
Europe PubMed Central
Article . 2015
Data sources: PubMed Central
image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
ACS Chemical Neuroscience
Article
License: CC BY
Data sources: UnpayWall
https://doi.org/10.7916/d86t0m...
Other literature type . 2015
Data sources: Datacite
versions View all 3 versions
addClaim

This Research product is the result of merged Research products in OpenAIRE.

You have already added 0 works in your ORCID record related to the merged Research product.
addClaim

This Research product is the result of merged Research products in OpenAIRE.

You have already added 0 works in your ORCID record related to the merged Research product.

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor That Attenuates Disease Progression in Alzheimer’s Disease Mouse Models

Authors: Saktimayee M, Roy; Valerie L, Grum-Tokars; James P, Schavocky; Faisal, Saeed; Agnieszka, Staniszewski; Andrew F, Teich; Ottavio, Arancio; +7 Authors

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor That Attenuates Disease Progression in Alzheimer’s Disease Mouse Models

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.

Subjects by Vocabulary

Microsoft Academic Graph classification: Pharmacology Tyrosine-kinase inhibitor Neuropharmacology Kinase Protein kinase inhibitor Alzheimer's disease Signal transduction Gene isoform medicine.drug_class Biology medicine Protein kinase A medicine.disease

Keywords

Male, Physiology, Drug Evaluation, Preclinical, Signal transduction, Biochemistry, Mitogen-Activated Protein Kinase 14, Rats, Sprague-Dawley, Pathology, Spatial Memory, Molecular Structure, Brain, Drugs, protein kinase, General Medicine, Pyridazines, Neuroprotective Agents, Disease Progression, Microsomes, Liver, Medicine, Mental health, Research Article, Cognitive Neuroscience, Mice, Transgenic, Cell Line, Alzheimer Disease, cognitive dysfunction, Animals, Humans, crystallography, Protein Kinase Inhibitors, Pharmacology, Memory Disorders, Dose-Response Relationship, Drug, Association Learning, Cell Biology, Disease Models, Animal, Synapses, chemical synthesis

34 references, page 1 of 4

U.S. Food and Drug Administration (2001) Novartis, NDA 021335.

Fabbro D., Cowan-Jacob S. W., Mobitz H., and Martiny-Baron G. (2012) Targeting cancer with small-molecular-weight kinase inhibitors. In Methods in Molecular Biology (Walker J. M., Ed.), 1 st ed., Vol. 795, pp 1–34, Humana Press, New York.

Rask-Andersen M.; Zhang J.; Fabbro D.; Schiöth H. B. (2014) Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol. Sci. 35, 604–620.25312588 [OpenAIRE] [PubMed]

O’Brien Z.; Moghaddam M. F. (2013) Small Molecule Kinase Inhibitors Approved by the FDA from 2000 to 2011: A Systematic review of preclinical ADME Data. Expert Opin. Drug Metabol. Toxicol. 9, 1597–1612.

Uitdehaag J. C.; Verkaar F.; Alwan H.; de Man J.; Buijsman R. C.; Zaman G. J. R. (2012) A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets. Br. J. Pharmacol. 166, 858–876.22250956 [OpenAIRE] [PubMed]

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. (2013) Development of novel in vivo chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS One 8, e66226.23840427 [OpenAIRE] [PubMed]

Pardridge W. M. (2005) Blood-brain barrier: Bottleneck in brain drug development. NeuroRx 2, 3–14.15717053 [OpenAIRE] [PubMed]

Munoz L.; Ammit A. J. (2010) Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 58, 561–568.19951717 [OpenAIRE] [PubMed]

Bachstetter A. D.; Watterson D. M.; Van Eldik L. J. (2014) Target engagement analysis and link to pharmacodynamics endpoint for a novel class of CNS-penetrant and efficacious p38α MAPK inhibitors. J. Neuroimmune Pharmacol. 9, 454–460.24789302 [OpenAIRE] [PubMed]

Chavkin C., Schattauer S. S., and Levin J. R. (2014) Arrestin-Mediated Activation of p38 MAPK: molecular mechanism and behavioral consequences. In Handbook of Experimental Pharmacology (Berlin W. R., Ed), 1 st ed, Vol. 219, pp 281–292, Springer Press, New York.

  • BIP!
    Impact byBIP!
    citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    76
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 1%
  • citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    76
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 1%
    Powered byBIP!BIP!
Powered by OpenAIRE graph
Found an issue? Give us feedback
citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
76
Top 10%
Top 10%
Top 1%
Green
hybrid
Funded by
NIH| Preclinical Alzheimers Disease Drug Development of Novel MAPK Inhibitors
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5U01AG043415-03
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| Development of Novel p38 MAPK Inhibitors as Therapeutics for CNS Disorders
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01AG031311-02
  • Funding stream: NATIONAL INSTITUTE ON AGING
iis
Related to Research communities
Neuroinformatics
moresidebar

Do the share buttons not appear? Please make sure, any blocking addon is disabled, and then reload the page.