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  1. AU="Maestre, Michael"
  2. AU="Kang, Adrian Ez"
  3. AU="Nolan, Mark"
  4. AU="Sangha, Sonia"
  5. AU="Shekhar, Nishant" AU="Shekhar, Nishant"
  6. AU="Barrington, Sally F"
  7. AU="Ríos, D Balaguer"
  8. AU="Aikaterini Emmanouilidi"
  9. AU="Rocha-Filho, Francisco Dário" AU="Rocha-Filho, Francisco Dário"
  10. AU="René F Ketting"
  11. AU="Mohammed, Shabber"
  12. AU="Frösen, Juhana"
  13. AU="Walter, Annette O"
  14. AU=de Groot Yorick J
  15. AU="Sánchez-González, Cristina"

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  1. Artikel ; Online: Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation.

    Johnson, Eric / McTigue, Michele / Gallego, Rebecca A / Johnson, Ted W / Timofeevski, Sergei / Maestre, Michael / Fisher, Timothy S / Kania, Robert / Sawasdikosol, Sansana / Burakoff, Steven / Cronin, Ciarán N

    The Journal of biological chemistry

    2019  Band 294, Heft 23, Seite(n) 9029–9036

    Abstract: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a Ser/Thr kinase that operates via the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways to dampen the T-cell response and antitumor immunity. ... ...

    Abstract Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a Ser/Thr kinase that operates via the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways to dampen the T-cell response and antitumor immunity. Accordingly, selective HPK1 inhibition is considered a means to enhance antitumor immunity. Sunitinib, a multi-receptor tyrosine kinase (RTK) inhibitor approved for the management of gastrointestinal stromal tumors (GISTs), renal cell carcinoma (RCC), and pancreatic cancer, has been reported to inhibit HPK1
    Mesh-Begriff(e) Adenosine Triphosphate/chemistry ; Adenosine Triphosphate/metabolism ; Binding Sites ; Crystallography, X-Ray ; Dimerization ; Humans ; Interleukin-2/metabolism ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Phosphorylation ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Sunitinib/chemistry ; Sunitinib/metabolism ; Sunitinib/pharmacology ; T-Lymphocytes/cytology ; T-Lymphocytes/drug effects ; T-Lymphocytes/metabolism
    Chemische Substanzen Interleukin-2 ; Recombinant Proteins ; Adenosine Triphosphate (8L70Q75FXE) ; hematopoietic progenitor kinase 1 (EC 2.7.1.11) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Sunitinib (V99T50803M)
    Sprache Englisch
    Erscheinungsdatum 2019-04-24
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.AC119.007466
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.

    Gallego, Rebecca A / Bernier, Louise / Chen, Hui / Cho-Schultz, Sujin / Chung, Loanne / Collins, Michael / Del Bel, Matthew / Elleraas, Jeff / Costa Jones, Cinthia / Cronin, Ciaran N / Edwards, Martin / Fang, Xu / Fisher, Timothy / He, Mingying / Hoffman, Jacqui / Huo, Ruiduan / Jalaie, Mehran / Johnson, Eric / Johnson, Ted W /
    Kania, Robert S / Kraus, Manfred / Lafontaine, Jennifer / Le, Phuong / Liu, Tongnan / Maestre, Michael / Matthews, Jean / McTigue, Michele / Miller, Nichol / Mu, Qiming / Qin, Xulong / Ren, Shijian / Richardson, Paul / Rohner, Allison / Sach, Neal / Shao, Li / Smith, Graham / Su, Ruirui / Sun, Bin / Timofeevski, Sergei / Tran, Phuong / Wang, Shuiwang / Wang, Wei / Zhou, Ru / Zhu, Jinjiang / Nair, Sajiv K

    Journal of medicinal chemistry

    2023  Band 66, Heft 7, Seite(n) 4888–4909

    Abstract: Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic ...

    Abstract Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized
    Mesh-Begriff(e) Humans ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; Pyrroles/pharmacology
    Chemische Substanzen hematopoietic progenitor kinase 1 (EC 2.7.1.11) ; pyrrolopyrimidine ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Pyrroles
    Sprache Englisch
    Erscheinungsdatum 2023-03-20
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.2c02038
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: TGFβ responsive tyrosine phosphatase promotes rheumatoid synovial fibroblast invasiveness.

    Stanford, Stephanie M / Aleman Muench, German R / Bartok, Beatrix / Sacchetti, Cristiano / Kiosses, William B / Sharma, Jay / Maestre, Michael F / Bottini, Massimo / Mustelin, Tomas / Boyle, David L / Firestein, Gary S / Bottini, Nunzio

    Annals of the rheumatic diseases

    2016  Band 75, Heft 1, Seite(n) 295–302

    Abstract: Objective: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) that line joint synovial membranes aggressively invade the extracellular matrix, destroying cartilage and bone. As signal transduction in FLS is mediated through multiple ... ...

    Abstract Objective: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) that line joint synovial membranes aggressively invade the extracellular matrix, destroying cartilage and bone. As signal transduction in FLS is mediated through multiple pathways involving protein tyrosine phosphorylation, we sought to identify protein tyrosine phosphatases (PTPs) regulating the invasiveness of RA FLS. We describe that the transmembrane receptor PTPκ (RPTPκ), encoded by the transforming growth factor (TGF) β-target gene, PTPRK, promotes RA FLS invasiveness.
    Methods: Gene expression was quantified by quantitative PCR. PTP knockdown was achieved using antisense oligonucleotides. FLS invasion and migration were assessed in transwell or spot assays. FLS spreading was assessed by immunofluorescence microscopy. Activation of signalling pathways was analysed by Western blotting of FLS lysates using phosphospecific antibodies. In vivo FLS invasiveness was assessed by intradermal implantation of FLS into nude mice. The RPTPκ substrate was identified by pull-down assays.
    Results: PTPRK expression was higher in FLS from patients with RA versus patients with osteoarthritis, resulting from increased TGFB1 expression in RA FLS. RPTPκ knockdown impaired RA FLS spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumour necrosis factor and interleukin 1 stimulation. Furthermore, RPTPκ deficiency impaired the in vivo invasiveness of RA FLS. Molecular analysis revealed that RPTPκ promoted RA FLS migration by dephosphorylation of the inhibitory residue Y527 of SRC.
    Conclusions: By regulating phosphorylation of SRC, RPTPκ promotes the pathogenic action of RA FLS, mediating cross-activation of growth factor and inflammatory cytokine signalling by TGFβ in RA FLS.
    Mesh-Begriff(e) Animals ; Arthritis, Rheumatoid/metabolism ; Arthritis, Rheumatoid/pathology ; Cell Movement/genetics ; Cell Movement/physiology ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Fibroblasts/physiology ; Fibroblasts/transplantation ; Gene Expression Regulation, Enzymologic/physiology ; Gene Knockdown Techniques ; Heterografts ; Humans ; Mice, Nude ; Protein Tyrosine Phosphatases/genetics ; Protein Tyrosine Phosphatases/physiology ; RNA, Messenger/genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/physiology ; Synovial Membrane/metabolism ; Synovial Membrane/pathology ; Synovial Membrane/transplantation ; Transforming Growth Factor beta1/physiology ; Up-Regulation
    Chemische Substanzen RNA, Messenger ; Transforming Growth Factor beta1 ; PTPRK protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; Receptor-Like Protein Tyrosine Phosphatases, Class 2 (EC 3.1.3.48)
    Sprache Englisch
    Erscheinungsdatum 2016-01
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 7090-7
    ISSN 1468-2060 ; 0003-4967
    ISSN (online) 1468-2060
    ISSN 0003-4967
    DOI 10.1136/annrheumdis-2014-205790
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

    Kiris, Erkan / Nuss, Jonathan E / Stanford, Stephanie M / Wanner, Laura M / Cazares, Lisa / Maestre, Michael F / Du, Hao T / Gomba, Glenn Y / Burnett, James C / Gussio, Rick / Bottini, Nunzio / Panchal, Rekha G / Kane, Christopher D / Tessarollo, Lino / Bavari, Sina

    PloS one

    2015  Band 10, Heft 6, Seite(n) e0129264

    Abstract: There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). ... ...

    Abstract There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s) of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs). Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists.
    Mesh-Begriff(e) Animals ; Botulinum Toxins/antagonists & inhibitors ; Botulinum Toxins/toxicity ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Embryonic Stem Cells/drug effects ; Embryonic Stem Cells/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Mice ; Motor Neurons/drug effects ; Motor Neurons/metabolism ; Phosphoric Monoester Hydrolases/antagonists & inhibitors ; SNARE Proteins/metabolism ; Small Molecule Libraries/pharmacology
    Chemische Substanzen Enzyme Inhibitors ; SNARE Proteins ; Small Molecule Libraries ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; Botulinum Toxins (EC 3.4.24.69)
    Sprache Englisch
    Erscheinungsdatum 2015-06-10
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0129264
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like synoviocytes: a novel role of SH2 domain-containing phosphatase 2 as a modulator of invasion and survival.

    Stanford, Stephanie M / Maestre, Michael F / Campbell, Amanda M / Bartok, Beatrix / Kiosses, William B / Boyle, David L / Arnett, Heather A / Mustelin, Tomas / Firestein, Gary S / Bottini, Nunzio

    Arthritis and rheumatism

    2013  Band 65, Heft 5, Seite(n) 1171–1180

    Abstract: Objective: The fibroblast-like synoviocytes (FLS) in the synovial intimal lining of the joint are key mediators of inflammation and joint destruction in rheumatoid arthritis (RA). In RA, these cells aggressively invade the extracellular matrix, ... ...

    Abstract Objective: The fibroblast-like synoviocytes (FLS) in the synovial intimal lining of the joint are key mediators of inflammation and joint destruction in rheumatoid arthritis (RA). In RA, these cells aggressively invade the extracellular matrix, producing cartilage-degrading proteases and inflammatory cytokines. The behavior of FLS is controlled by multiple interconnected signal transduction pathways involving reversible phosphorylation of proteins on tyrosine residues. However, little is known about the role of the protein tyrosine phosphatases (PTPs) in FLS function. This study was undertaken to explore the expression of all of the PTP genes (the PTPome) in FLS.
    Methods: A comparative screening of the expression of the PTPome in FLS from patients with RA and patients with osteoarthritis (OA) was conducted. The functional effect on RA FLS of SH2 domain-containing phosphatase 2 (SHP-2), a PTP that was up-regulated in RA, was then analyzed by knockdown using cell-permeable antisense oligonucleotides.
    Results: PTPN11 was overexpressed in RA FLS compared to OA FLS. Knockdown of PTPN11, which encodes SHP-2, reduced the invasion, migration, adhesion, spreading, and survival of RA FLS. Additionally, signaling in response to growth factors and inflammatory cytokines was impaired by SHP-2 knockdown. RA FLS that were deficient in SHP-2 exhibited decreased activation of focal adhesion kinase and mitogen-activated protein kinases.
    Conclusion: These findings indicate that SHP-2 has a novel role in mediating human FLS function and suggest that it promotes the invasiveness and survival of RA FLS. Further investigation may reveal SHP-2 to be a candidate therapeutic target for RA.
    Mesh-Begriff(e) Arthritis, Rheumatoid/enzymology ; Arthritis, Rheumatoid/genetics ; Cell Line ; Cell Movement ; Fibroblasts/enzymology ; Fibroblasts/pathology ; Gene Expression Regulation, Enzymologic ; Gene Knockdown Techniques ; Humans ; Oligonucleotides, Antisense/pharmacology ; Osteoarthritis/enzymology ; Osteoarthritis/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism ; Protein Tyrosine Phosphatases/genetics ; Protein Tyrosine Phosphatases/metabolism ; Signal Transduction ; Synovial Membrane/enzymology ; Synovial Membrane/pathology ; Up-Regulation
    Chemische Substanzen Oligonucleotides, Antisense ; PTPN11 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
    Sprache Englisch
    Erscheinungsdatum 2013-02-25
    Erscheinungsland United States
    Dokumenttyp Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 127294-9
    ISSN 1529-0131 ; 0004-3591 ; 2326-5191
    ISSN (online) 1529-0131
    ISSN 0004-3591 ; 2326-5191
    DOI 10.1002/art.37872
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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