Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction
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{"title"=>"Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction", "type"=>"journal", "authors"=>[{"first_name"=>"D. Martin", "last_name"=>"Watterson", "scopus_author_id"=>"7006284890"}, {"first_name"=>"Valerie L.", "last_name"=>"Grum-Tokars", "scopus_author_id"=>"6507693054"}, {"first_name"=>"Saktimayee M.", "last_name"=>"Roy", "scopus_author_id"=>"15763783300"}, {"first_name"=>"James P.", "last_name"=>"Schavocky", "scopus_author_id"=>"6505852960"}, {"first_name"=>"Brindasai", "last_name"=>"de Bradaric", "scopus_author_id"=>"55777893200"}, {"first_name"=>"Adam D.", "last_name"=>"Bachstetter", "scopus_author_id"=>"6505466824"}, {"first_name"=>"Bin", "last_name"=>"Xing", "scopus_author_id"=>"36018832300"}, {"first_name"=>"Edgardo", "last_name"=>"Dimayuga", "scopus_author_id"=>"6603118306"}, {"first_name"=>"Faisal", "last_name"=>"Saeed", "scopus_author_id"=>"54080298800"}, {"first_name"=>"Hong", "last_name"=>"Zhang", "scopus_author_id"=>"56965798300"}, {"first_name"=>"Agnieszka", "last_name"=>"Staniszewski", "scopus_author_id"=>"8637293400"}, {"first_name"=>"Jeffrey C.", "last_name"=>"Pelletier", "scopus_author_id"=>"57196674997"}, {"first_name"=>"George", "last_name"=>"Minasov", "scopus_author_id"=>"6603737810"}, {"first_name"=>"Wayne F.", "last_name"=>"Anderson", "scopus_author_id"=>"55206058200"}, {"first_name"=>"Ottavio", "last_name"=>"Arancio", "scopus_author_id"=>"7003543010"}, {"first_name"=>"Linda J.", "last_name"=>"van Eldik", "scopus_author_id"=>"7006411314"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"23840427", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pui"=>"369203084", "sgr"=>"84879526339", "scopus"=>"2-s2.0-84879526339", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0066226"}, "id"=>"f8bc974a-f1b1-3a9d-b651-91326c5da111", "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.", "link"=>"http://www.mendeley.com/research/development-novel-vivo-chemical-probes-address-cns-protein-kinase-involvement-synaptic-dysfunction", "reader_count"=>23, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. 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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1102476"], "description"=>"<p>The title compounds were characterized in terms of their physical characteristics, target selectivity, and pharmacological properties.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "selective", "inhibitors", "mw108", "mw181"], "article_id"=>732640, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g002", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_selective_p38_945_MAPK_inhibitors_MW108_panel_A_and_MW181_panel_B_/732640", "title"=>"Characterization of selective p38αMAPK inhibitors MW108 (panel A) and MW181 (panel B).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102485", "https://ndownloader.figshare.com/files/1102486", "https://ndownloader.figshare.com/files/1102487", "https://ndownloader.figshare.com/files/1102488", "https://ndownloader.figshare.com/files/1102489", "https://ndownloader.figshare.com/files/1102490"], "description"=>"<div><p>Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for <i>in vivo</i> investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show <i>in vivo</i> 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 <i>in vivo</i> modulation of their catalytic activity. Identification of molecular targets whose <i>in vivo</i> 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 <i>in vivo</i> 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. <i>In vitro</i> and <i>in vivo</i> 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 <i>in vivo</i> probes appropriate for CNS investigations and demonstrate that modulation of p38αMAPK activity can attenuate synaptic dysfunction.</p></div>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "probes", "cns", "kinase", "synaptic", "dysfunction"], "article_id"=>732649, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0066226.s001", "https://dx.doi.org/10.1371/journal.pone.0066226.s002", "https://dx.doi.org/10.1371/journal.pone.0066226.s003", "https://dx.doi.org/10.1371/journal.pone.0066226.s004", "https://dx.doi.org/10.1371/journal.pone.0066226.s005", "https://dx.doi.org/10.1371/journal.pone.0066226.s006"], "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Development_of_Novel_In_Vivo_Chemical_Probes_to_Address_CNS_Protein_Kinase_Involvement_in_Synaptic_Dysfunction/732649", "title"=>"Development of Novel <i>In Vivo</i> Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102483"], "description"=>"<p><b>A.</b> MW181 ameliorated the LTP deficit in Aβ<sub>42</sub>-treated slices (n = 7–8 slices/group; F(1,13) = 6.651, p = 0.0229, compared to slices treated only with Aβ<sub>42</sub>). Horizontal bar = time of application of Aβ<sub>42</sub> and MW181. <b>B.</b> MW181 ameliorated the reference memory deficit in Aβ<sub>42</sub>-infused mice (n = 10 mice/group; F(1,18) = 5.851, p = 0.0264 comparing Aβ-infused vs. Aβ-infused+compound). <b>C.</b> MW-181 ameliorated the contextual fear memory deficit in Aβ<sub>42</sub>-infused mice (n = 15–16 mice/group; p = 0.0005 comparing Aβ-infused vs. Aβ-infused+compound). <b>D-E.</b> No difference was detected between groups when tested for visual-motor-motivational deficits with the visible platform test; speed and time to the platform are shown in D and E, respectively (n = 10 mice/group). <b>F.</b> The same animals that underwent contextual fear conditioning testing were assessed for cued learning 24 hrs after the contextual learning. No difference was detected between groups (n = 15–16 mice/group). <b>G.</b> Sensory threshold was not affected regardless of treatment (n = 9 mice/group). <b>H-I.</b> No differences in exploratory behavior, as shown by a similar percentage of time spent in the center compartment (H) and the number of entries into the center compartment (I), were observed (n = 9 mice/group).</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "synaptic", "dysfunction", "mw181"], "article_id"=>732647, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g009", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Attenuation_of_A_42_induced_synaptic_and_cognitive_dysfunction_by_MW181_administration_/732647", "title"=>"Attenuation of Aβ<sub>42</sub>-induced synaptic and cognitive dysfunction by MW181 administration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102484"], "description"=>"<p>Data collection and phasing statistics. Values in parentheses are for highest resolution shell.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "phasing", "parentheses", "highest"], "article_id"=>732648, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.t001", "stats"=>{"downloads"=>0, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Data_collection_and_phasing_statistics_Values_in_parentheses_are_for_highest_resolution_shell_/732648", "title"=>"Data collection and phasing statistics. Values in parentheses are for highest resolution shell.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102482"], "description"=>"<p><b>A.</b> MW108 ameliorated the LTP deficit in Aβ<sub>42</sub>-treated slices (n = 7–8 slices/group; F(1,13) = 17.25, p = 0.0011, compared to slices treated only with Aβ<sub>42</sub>). Horizontal bar = time of application of Aβ<sub>42</sub> and MW108. <b>B.</b> MW108 ameliorated the reference memory deficit in Aβ<sub>42</sub>-infused mice (n = 10–14 mice/group; F(1,24) = 1.827, p = 0.0001 comparing Aβ-infused vs. Aβ-infused+compound). <b>C.</b> MW108 ameliorated the contextual fear memory deficit in Aβ<sub>42</sub>-infused mice (n = 16-18 mice/group; p = 0.009 comparing Aβ-infused vs. Aβ-infused+compound). <b>D-E.</b> No difference was detected between groups when tested for visual-motor-motivational deficits with the visible platform test; speed and time to the platform are shown in D and E, respectively (n = 10–14 mice/group). <b>F.</b> The same animals that underwent contextual fear conditioning testing were assessed for cued learning 24 hrs after the contextual learning. No difference was detected between groups (n = 16–18 mice/group). <b>G.</b> Sensory threshold was not affected regardless of treatment (n = 13–17 mice/group). <b>H-I.</b> No differences in exploratory behavior, as shown by a similar percentage of time spent in the center compartment (H) and the number of entries into the center compartment (I), were observed (n = 13–17 mice/group).</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "synaptic", "dysfunction", "mw108"], "article_id"=>732646, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g008", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Attenuation_of_A_42_induced_synaptic_and_cognitive_dysfunction_by_MW108_administration_/732646", "title"=>"Attenuation of Aβ<sub>42</sub>-induced synaptic and cognitive dysfunction by MW108 administration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102479"], "description"=>"<p><b>A.</b> Electron density maps (2mFo-Dfc; colored in light gray) contoured at 1.5 rmsd for the hinge region of p38αMAPK near Gly110 for 4F9W (in complex with MW108) and for 4FA2 (in complex with SB239063) are shown. Differences in the electron density path are seen in the area around Gly110, indicated by arrows. <b>B.</b> A superposition of 4F9W and 4FA2 reveals the differences around the peptide bond at Met109-Gly110, referred to as a glycine flip for structures such as 4FA2.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "conformational", "hinge", "non-selective", "inhibitor"], "article_id"=>732643, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g005", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Localized_conformational_change_in_the_hinge_region_of_human_p38_945_MAPK_when_a_non_selective_inhibitor_is_bound_/732643", "title"=>"Localized conformational change in the hinge region of human p38αMAPK when a non-selective inhibitor is bound.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102478"], "description"=>"<p><b>A.</b> The 2.00Å structure (4F9W) of human p38αMAPK (cyan ribbons) containing MW108 (colored by atom type) bound in the active site is shown. The typical kinase bi-lobed nature is evident, with the hinge region connecting the two lobes of the kinase indicated by the arrow. <b>B.</b> A Connolly surface generated from the coordinates of 4F9W highlights the complementary features between MW108 and the kinase active site. <b>C.</b> Electron density map (2mFo-Dfc) for 4F9W contoured at a 1.5 rmsd level. The diffraction data clearly reveals the inhibitor presence in the active site. The relative positions of Met 109 in the hinge region and the hydrophobic pocket’s small gatekeeper residue Thr 106 are indicated by arrows. The pyridine ring nitrogen of MW108 makes H-bond interactions with the protein backbone at the Met109-Gly110 peptide bond. <b>D.</b> The 1.85Å resolution structure (4F9Y) of human p38αMAPK (cyan ribbons) with MW181 (colored by atom type) bound in the active site is shown, with the hinge region indicated by the arrow. <b>E.</b> A Connolly surface generated from the coordinates of 4F9Y highlights the complementary features between MW181 and the kinase active site. <b>F.</b> Electron density map (2mF0-Dfc) for 4F9Y contoured at 1.5 rmsd. The difference in orientation of the1-naphthyl substituent in MW181 4F9Y from that of the 2-naphthyl substituent in MW108 4F9W (Panel C) is evident from the diffraction data.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "structures", "mw108", "mw181", "bound"], "article_id"=>732642, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g004", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Crystal_structures_of_human_p38_945_MAPK_with_MW108_PDB_4F9W_or_MW181_PDB_4F9Y_bound_in_the_active_site_/732642", "title"=>"Crystal structures of human p38αMAPK with MW108 (PDB 4F9W) or MW181 (PDB 4F9Y) bound in the active site.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102481"], "description"=>"<p><b>A.</b> MW181 inhibited phosphorylation of the p38αMAPK substrate MK2 in a concentration-dependent manner in LPS-stimulated BV-2 microglial cells. <b>B.</b> MW181 inhibited LPS-induced IL-1β production in a concentration-dependent manner in BV-2 cells. <b>C.</b> MW-181 suppressed IL-1β production in BV-2 cells stimulated with diverse TLR ligands. BV-2 cells were treated with ligands for TLR2, TLR4, TLR7/8, and TLR9 in the absence (white bars) or presence (gray bars) of MW181. ‡ <i>p</i><0.0001 compared to TLR ligand in the absence of compound. <b>D.</b> MW181 inhibited LPS-induced IL-1β production in primary microglia from wild-type (WT) mice, but not from drug-resistant p38αMAPK knock-in (p38α KI) mice. # <i>p</i><0.01, § <i>p</i><0.001 compared to LPS alone. <b>E.</b> MW181 suppressed LPS-induced IL-1β levels <i>in vivo</i>. **<i>p</i><0.01 compared to LPS alone (n = 6 saline/vehicle; n = 24 LPS/vehicle; n = 15 LPS/MW181). Data in all panels are expressed as a percent of the maximal levels, where levels in the presence of stressor alone were normalized to 100%.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry"], "article_id"=>732645, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g007", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cellular_target_engagement_and_mechanism_of_action_of_MW181_/732645", "title"=>"Cellular target engagement and mechanism of action of MW181.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102480"], "description"=>"<p><b>A.</b> MW108 inhibited phosphorylation of the p38α substrate MK2 in a concentration-dependent manner in LPS-stimulated BV-2 microglial cells. <b>B.</b> MW108 inhibited LPS-induced IL-1β production in a concentration-dependent manner in BV-2 cells. <b>C.</b> MW108 suppressed IL-1β production in BV-2 cells stimulated with diverse TLR ligands. BV-2 cells were treated with ligands for TLR2, TLR4, TLR7/8, and TLR9 in the absence (white bars) or presence (gray bars) of MW108. ‡ <i>p</i><0.0001 compared to TLR ligand in the absence of compound. <b>D.</b> MW108 inhibited LPS-induced IL-1β production in primary microglia from wild-type (WT) mice, but not from drug-resistant p38αMAPK knock-in (p38α KI) mice. # <i>p</i><0.01, § <i>p</i><0.001 compared to LPS alone. <b>E.</b> MW108 suppressed LPS-induced IL-1β levels <i>in vivo</i>. **<i>p</i><0.01 compared to LPS alone (n = 6 saline/vehicle; n = 24 LPS/vehicle; n = 15 LPS/MW108). Data in all panels are expressed as a percent of the maximal levels, where levels in the presence of stressor alone were normalized to 100%.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry"], "article_id"=>732644, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g006", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cellular_target_engagement_and_mechanism_of_action_of_MW108_/732644", "title"=>"Cellular target engagement and mechanism of action of MW108.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102477"], "description"=>"<p>The affinity of compounds for p38αMAPK and CK1δ is shown, as well as the highest dose at which no adverse events are observed in dose escalation studies.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "inhibitor", "analogs", "screens", "differential", "inhibition"], "article_id"=>732641, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synthesis_of_p38_945_MAPK_inhibitor_analogs_and_initial_screens_for_differential_p38_945_MAPK_vs_CK1_948_inhibition_and_for_improvement_in_high_dose_tolerance_/732641", "title"=>"Synthesis of p38αMAPK inhibitor analogs and initial screens for differential p38αMAPK vs CK1δ inhibition and for improvement in high dose tolerance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1102475"], "description"=>"<p>Reagents and conditions: i) Hydrazine sulphate, H<sub>2</sub>O, 100°C; ii) Pyridin-4-ylboronic acid; 1,2-dimethoxyethane (DME)/water, Na<sub>2</sub>CO<sub>3</sub>, Pd(PPh<sub>3</sub>)<sub>4</sub>, 110°C; iii) phosphorus oxychloride/acetonitrile, 90°C; iv) Ethanol, amine, reflux; v) 1- or 2- Naphthylboronic acid, DME/water, Na<sub>2</sub>CO<sub>3</sub>, Pd(PPh<sub>3</sub>)<sub>4</sub>, 110°C; vi) concentrated HCl, anhydrous isopropanol, 80°C.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "Signaling cascades", "MAPK signaling cascades", "Protein kinase signaling cascade", "Signaling in selected disciplines", "Neurological signaling", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Learning and memory", "Neurobiology of disease and regeneration", "chemical biology", "medicinal chemistry", "Drugs and devices", "Pharmacodynamics", "neurology", "dementia", "Alzheimer disease", "Neurodegenerative diseases", "biophysics", "Biomacromolecule-ligand interactions", "Protein chemistry", "synthetic"], "article_id"=>732639, "categories"=>["Physics", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["D. Martin Watterson", "Valerie L. Grum-Tokars", "Saktimayee M. Roy", "James P. Schavocky", "Brinda Desai Bradaric", "Adam D. Bachstetter", "Bin Xing", "Edgardo Dimayuga", "Faisal Saeed", "Hong Zhang", "Agnieszka Staniszewski", "Jeffrey C. Pelletier", "George Minasov", "Wayne F. Anderson", "Ottavio Arancio", "Linda J. Van Eldik"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066226.g001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Discovery_synthetic_scheme_for_title_compounds_/732639", "title"=>"Discovery synthetic scheme for title compounds.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-26 09:33:41"}

PMC Usage Stats | Further Information

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Relative Metric

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