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PDBsum entry 4r3c
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Transferase/transferase inhibitor
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PDB id
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4r3c
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References listed in PDB file
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Key reference
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Title
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Targeting human central nervous system protein kinases: an isoform selective p38αmapk inhibitor that attenuates disease progression in alzheimer'S disease mouse models.
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Authors
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S.M.Roy,
V.L.Grum-Tokars,
J.P.Schavocky,
F.Saeed,
A.Staniszewski,
A.F.Teich,
O.Arancio,
A.D.Bachstetter,
S.J.Webster,
L.J.Van eldik,
G.Minasov,
W.F.Anderson,
J.C.Pelletier,
D.M.Watterson.
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Ref.
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Acs Chem Neurosci, 2015,
6,
666-680.
[DOI no: ]
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PubMed id
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Abstract
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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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