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  1. AU="Shillingford, Shanelle R"
  2. AU="Ahn, Sung Soo"
  3. AU="Salih, Harith M"
  4. AU="Clayton, Philip A"
  5. AU="Soto, A. Garcia"
  6. AU="Jones, Daniel OB"
  7. AU="Chen, Maosheng"
  8. AU="Li, Zhengxi"
  9. AU="Toshiya Takahashi"
  10. AU=Hickey Chelsea L.
  11. AU="Badhrinarayanan, Shreya"
  12. AU="Milani, Liliana"
  13. AU="Reinhardt, Klaus"
  14. AU="Caudillo-Flores, Uriel"
  15. AU="Yin, Yizhen"
  16. AU=Kaushansky Kenneth
  17. AU="Golla, Jaya Prakash"
  18. AU="Penn, Marc S"
  19. AU="Montero, Vincent"
  20. AU="Etevenon, Pierre"
  21. AU="Hyseni, Agon"
  22. AU="Seitzman, Natalie"
  23. AU="Loukil, Abdelhalim"
  24. AU="Giammusso, Bruno"
  25. AU="Kaplan, Jonathan E"
  26. AU=Francolini Giulio
  27. AU="Yuhu Li"
  28. AU=Kim Moojung
  29. AU="Vise, Luciana M"
  30. AU="Marcinowska, Zuzanna"
  31. AU="Graff, Pablo"

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  1. Artikel ; Online: Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?

    Shillingford, Shanelle R / Bennett, Anton M

    Annual review of pharmacology and toxicology

    2023  Band 63, Seite(n) 617–636

    Abstract: Phosphatases and kinases maintain an equilibrium of dephosphorylated and phosphorylated proteins, respectively, that are required for critical cellular functions. Imbalance in this equilibrium or irregularity in their function causes unfavorable cellular ...

    Abstract Phosphatases and kinases maintain an equilibrium of dephosphorylated and phosphorylated proteins, respectively, that are required for critical cellular functions. Imbalance in this equilibrium or irregularity in their function causes unfavorable cellular effects that have been implicated in the development of numerous diseases. Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of protein substrates on tyrosine residues, and their involvement in cell signaling and diseases such as cancer and inflammatory and metabolic diseases has made them attractive therapeutic targets. However, PTPs have proved challenging in therapeutics development, garnering them the unfavorable reputation of being undruggable. Nonetheless, great strides have been made toward the inhibition of PTPs over the past decade. Here, we discuss the advancement in small-molecule inhibition for the PTP subfamily known as the mitogen-activated protein kinase (MAPK) phosphatases (MKPs). We review strategies and inhibitor discovery tools that have proven successful for small-molecule inhibition of the MKPs and discuss what the future of MKP inhibition potentially might yield.
    Mesh-Begriff(e) Humans ; Mitogen-Activated Protein Kinase Phosphatases/antagonists & inhibitors ; Neoplasms/drug therapy ; Protein Tyrosine Phosphatases/antagonists & inhibitors ; Protein Tyrosine Phosphatases/metabolism ; Signal Transduction ; Tyrosine Kinase Inhibitors/chemistry ; Tyrosine Kinase Inhibitors/pharmacology
    Chemische Substanzen Mitogen-Activated Protein Kinase Phosphatases (EC 3.1.3.16) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; Tyrosine Kinase Inhibitors
    Sprache Englisch
    Erscheinungsdatum 2023-03-21
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 196587-6
    ISSN 1545-4304 ; 0362-1642
    ISSN (online) 1545-4304
    ISSN 0362-1642
    DOI 10.1146/annurev-pharmtox-051921-121923
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.

    Gannam, Zira T K / Jamali, Haya / Kweon, Oh Sang / Herrington, James / Shillingford, Shanelle R / Papini, Christina / Gentzel, Erik / Lolis, Elias / Bennett, Anton M / Ellman, Jonathan A / Anderson, Karen S

    European journal of medicinal chemistry

    2022  Band 243, Seite(n) 114712

    Abstract: Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease ... ...

    Abstract Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease a fatal rare disease which has neither a treatment nor cure. In previous work, we identified Compound 1 (3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one) as the lead compound of a novel class of MKP5 inhibitors. In this work, we explore the structure-activity relationship for inhibition of MKP5 through modifications to the scaffold and functional groups present in 1. A series of derivative compounds was designed, synthesized, and evaluated for inhibition of MKP5. In addition, the X-ray crystal structures of six enzyme-inhibitor complexes were solved, further elucidating the necessary requirements for MKP5 inhibition. We found that the parallel-displaced π-π interaction between the inhibitor three-ring core and Tyr435 is critical for modulating potency, and that modifications to the core and functionalization at the C-9 position are essential for ensuring proper positioning of the core for this interaction. These results lay the foundation from which more potent MKP5 allosteric inhibitors can be developed for potential therapeutics towards the treatment of dystrophic muscle disease.
    Mesh-Begriff(e) Structure-Activity Relationship
    Sprache Englisch
    Erscheinungsdatum 2022-09-02
    Erscheinungsland France
    Dokumenttyp Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2022.114712
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Zs.B 784: Hefte anzeigen Standort:
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  3. Artikel ; Online: An allosteric site on MKP5 reveals a strategy for small-molecule inhibition.

    Gannam, Zira T K / Min, Kisuk / Shillingford, Shanelle R / Zhang, Lei / Herrington, James / Abriola, Laura / Gareiss, Peter C / Pantouris, Georgios / Tzouvelekis, Argyrios / Kaminski, Naftali / Zhang, Xinbo / Yu, Jun / Jamali, Haya / Ellman, Jonathan A / Lolis, Elias / Anderson, Karen S / Bennett, Anton M

    Science signaling

    2020  Band 13, Heft 646

    Abstract: The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered "undruggable," but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of ...

    Abstract The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered "undruggable," but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of dystrophic muscle disease. Here, we identified an inhibitor of MKP5 using a p38α MAPK-derived, phosphopeptide-based small-molecule screen. We solved the structure of MKP5 in complex with this inhibitor, which revealed a previously undescribed allosteric binding pocket. Binding of the inhibitor to this pocket collapsed the MKP5 active site and was predicted to limit MAPK binding. Treatment with the inhibitor recapitulated the phenotype of MKP5 deficiency, resulting in activation of p38 MAPK and JNK. We demonstrated that MKP5 was required for TGF-β1 signaling in muscle and that the inhibitor blocked TGF-β1-mediated Smad2 phosphorylation. TGF-β1 pathway antagonism has been proposed for the treatment of dystrophic muscle disease. Thus, allosteric inhibition of MKP5 represents a therapeutic strategy against dystrophic muscle disease.
    Mesh-Begriff(e) Allosteric Site/genetics ; Amino Acid Sequence ; Animals ; Cell Differentiation/drug effects ; Cell Line ; Dual-Specificity Phosphatases/antagonists & inhibitors ; Dual-Specificity Phosphatases/chemistry ; Dual-Specificity Phosphatases/metabolism ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Female ; High-Throughput Screening Assays/methods ; Humans ; Kinetics ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinase Phosphatases/antagonists & inhibitors ; Mitogen-Activated Protein Kinase Phosphatases/chemistry ; Mitogen-Activated Protein Kinase Phosphatases/metabolism ; Myoblasts/cytology ; Myoblasts/drug effects ; Myoblasts/metabolism ; Protein Binding/drug effects ; Sequence Homology, Amino Acid ; Signal Transduction/drug effects ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism ; Small Molecule Libraries/pharmacology
    Chemische Substanzen Enzyme Inhibitors ; Small Molecule Libraries ; DUSP10 protein, human (EC 3.1.3.16) ; Mitogen-Activated Protein Kinase Phosphatases (EC 3.1.3.16) ; Dual-Specificity Phosphatases (EC 3.1.3.48)
    Sprache Englisch
    Erscheinungsdatum 2020-08-25
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.aba3043
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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