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

Journal Article · · ACS Chemical Neuroscience
 [1];  [1];  [1];  [2];  [2];  [2];  [2];  [3];  [3];  [3];  [1];  [1];  [1];  [1]
  1. Northwestern Univ., Evanston, IL (United States)
  2. Columbia Univ., New York, NY (United States)
  3. Univ. of Kentucky, Lexington, KY (United States)
+ Show Author Affiliations

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

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE
OSTI ID:
1498375
Journal Information:
ACS Chemical Neuroscience, Vol. 6, Issue 4; ISSN 1948-7193
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 64 works
Citation information provided by
Web of Science

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A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model journal January 2007
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Systems Biology and Pharmacology journal July 2010
Targeting protein kinases in central nervous system disorders journal November 2009
Opposing roles of p38 and JNK in a Drosophila model of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic components of neurodegeneration journal October 2014
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Cited By (32)

SB203580 reverses memory deficits and depression-like behavior induced by microinjection of Aβ1–42 into hippocampus of mice journal August 2016
Neuronal MAP kinase p38α inhibits c-Jun N-terminal kinase to modulate anxiety-related behaviour journal September 2018
Protein misfolding in neurodegenerative diseases: implications and strategies journal March 2017
Activation of EP 2 receptor suppresses poly(I: C) and LPS-mediated inflammation in primary microglia and organotypic hippocampal slice cultures: Contributing role for MAPKs journal December 2017
An exploratory clinical study of p38 α kinase inhibition in Alzheimer's disease journal March 2018
Tau Proteins and Tauopathies in Alzheimer’s Disease journal January 2018
Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS journal May 2018
Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer’s disease journal September 2016
Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling β-amyloid production journal March 2017
Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease journal January 2018
p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse journal October 2018
p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes journal August 2016
Neuronal p38α mediates age‐associated neural stem cell exhaustion and cognitive decline journal September 2019
Hippocampal metabotropic glutamate receptor long-term depression in health and disease: focus on mitogen-activated protein kinase pathways journal May 2016
Targeting innate immunity for neurodegenerative disorders of the central nervous system journal August 2016
Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes journal April 2017
Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology journal December 2016
Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer’s disease text January 2016
An exploratory clinical study of p38 α kinase inhibition in Alzheimer's disease journal March 2018
A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction journal April 2019
ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation journal March 2017
Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling β-amyloid production journal March 2017
p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse journal October 2018
Neuronal p38α mediates age‐associated neural stem cell exhaustion and cognitive decline journal September 2019
Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes journal April 2017
Protein misfolding in neurodegenerative diseases: implications and strategies journal March 2017
MW151 Inhibited IL-1β Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses journal February 2016
Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling posted_content February 2020
Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats journal August 2015
Defects in Axonal Transport in Inherited Neuropathies journal October 2019
p38α MAPK and Type I Inhibitors: Binding Site Analysis and Use of Target Ensembles in Virtual Screening journal August 2015
Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer’s disease text January 2016

Figures / Tables (14)

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