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  1. Article ; Online: Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

    Day, James E H / Berdini, Valerio / Castro, Joan / Chessari, Gianni / Davies, Thomas G / Day, Philip J / St Denis, Jeffrey D / Fujiwara, Hideto / Fukaya, Satoshi / Hamlett, Christopher C F / Hearn, Keisha / Hiscock, Steven D / Holvey, Rhian S / Ito, Satoru / Kandola, Navrohit / Kodama, Yasuo / Liebeschuetz, John W / Martins, Vanessa / Matsuo, Kenichi /
    Mortenson, Paul N / Muench, Sandra / Nakatsuru, Yoko / Ochiiwa, Hiroaki / Palmer, Nicholas / Peakman, Torren / Price, Amanda / Reader, Michael / Rees, David C / Rich, Sharna J / Shah, Alpesh / Shibata, Yoshihiro / Smyth, Tomoko / Twigg, David G / Wallis, Nicola G / Williams, Glyn / Wilsher, Nicola E / Woodhead, Andrew / Shimamura, Tadashi / Johnson, Christopher N

    Journal of medicinal chemistry

    2024  Volume 67, Issue 6, Page(s) 4655–4675

    Abstract: The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 ... ...

    Abstract The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.
    MeSH term(s) Humans ; Mice ; Animals ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Signal Transduction ; Receptor Protein-Tyrosine Kinases/metabolism ; Neoplasms ; Allosteric Site
    Chemical Substances Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
    Language English
    Publishing date 2024-03-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c02118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  2. Article ; Online: Unbiased Analysis of the Impact of Micropatterned Biomaterials on Macrophage Behavior Provides Insights beyond Predefined Polarization States.

    Singh, Sonali / Awuah, Dennis / Rostam, Hassan M / Emes, Richard D / Kandola, Navrohit K / Onion, David / Htwe, Su Su / Rajchagool, Buddharaksa / Cha, Byung-Hyun / Kim, Duckjin / Tighe, Patrick J / Vrana, Nihal E / Khademhosseini, Ali / Ghaemmaghami, Amir

    ACS biomaterials science & engineering

    2017  Volume 3, Issue 6, Page(s) 969–978

    Abstract: Macrophages are master regulators of immune responses toward implanted biomaterials. The activation state adopted by macrophages in response to biomaterials determines their own phenotype and function as well as those of other resident and infiltrating ... ...

    Abstract Macrophages are master regulators of immune responses toward implanted biomaterials. The activation state adopted by macrophages in response to biomaterials determines their own phenotype and function as well as those of other resident and infiltrating immune and nonimmune cells in the area. A wide spectrum of macrophage activation states exists, with M1 (pro-inflammatory) and M2 (anti-inflammatory) representing either ends of the spectrum. In biomaterials research, cell-instructive surfaces that favor or induce M2 macrophages have been considered as beneficial due to the anti-inflammatory and pro-regenerative properties of these cells. In this study, we used a gelatin methacryloyl (GelMA) hydrogel platform to determine whether micropatterned surfaces can modulate the phenotype and function of human macrophages. The effect of microgrooves/ridges and micropillars on macrophage phenotype, function, and gene expression profile were assessed using conventional methods (morphology, cytokine profile, surface marker expression, phagocytosis) and gene microarrays. Our results demonstrated that micropatterns did induce distinct gene expression profiles in human macrophages cultured on microgrooves/ridges and micropillars. Significant changes were observed in genes related to primary metabolic processes such as transcription, translation, protein trafficking, DNA repair, and cell survival. However, interestingly conventional phenotyping methods, relying on surface marker expression and cytokine profile, were not able to distinguish between the different conditions, and indicated no clear shift in cell activation towards M1 or M2 phenotypes. This highlights the limitations of studying the effect of different physicochemical conditions on macrophages by solely relying on conventional markers that are primarily developed to differentiate between cytokine polarized M1 and M2 macrophages. We therefore propose the adoption of unbiased screening methods in determining macrophage responses to biomaterials. Our data clearly show that the exclusive use of conventional markers and methods for determining macrophage activation status could lead to missed opportunities for understanding and exploiting macrophage responses to biomaterials.
    Language English
    Publishing date 2017-05-01
    Publishing country United States
    Document type Journal Article
    ISSN 2373-9878
    ISSN (online) 2373-9878
    DOI 10.1021/acsbiomaterials.7b00104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: In Vitro Methods for Studying the Mechanisms of Resistance to DNA-Damaging Therapeutic Drugs.

    Khongkow, Pasarat / Middleton, Anna W / Middleton, Anna K / Wong, Jocelyn P-M / Kandola, Navrohit K / Kongsema, Mesayamas / de Moraes, Gabriela Nestal / Gomes, Ana R / Lam, Eric W-F

    Methods in molecular biology (Clifton, N.J.)

    2016  Volume 1395, Page(s) 39–53

    Abstract: Most commonly used anticancer drugs exert their effects mainly by causing DNA damage. The enhancement in DNA damage response (DDR) is considered a key mechanism that enables cancer cells to survive through eliminating the damaged DNA lesions and thereby ... ...

    Abstract Most commonly used anticancer drugs exert their effects mainly by causing DNA damage. The enhancement in DNA damage response (DDR) is considered a key mechanism that enables cancer cells to survive through eliminating the damaged DNA lesions and thereby developing resistance to DNA-damaging agents. This chapter describes the four experimental approaches for studying DDR and genotoxic drug resistance, including the use of γ-H2AX and comet assays to monitor DNA damage and repair capacity as well as the use of clonogenic and β-galactosidase staining assays to assess long-term cell fate after DNA-damaging treatment. Finally, we also present examples of these methods currently used in our laboratory for studying the role of FOXM1 in DNA damage-induced senescence and epirubicin resistance.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Comet Assay/methods ; DNA Damage ; Drug Resistance, Neoplasm ; Electrophoresis ; Fluorescent Antibody Technique/methods ; Histones/metabolism ; Humans ; MCF-7 Cells ; Staining and Labeling ; beta-Galactosidase/metabolism
    Chemical Substances Antineoplastic Agents ; H2AX protein, human ; Histones ; beta-Galactosidase (EC 3.2.1.23)
    Language English
    Publishing date 2016-02-24
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-3347-1_3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Erratum to: In Vitro Methods for Studying the Mechanisms of Resistance to DNA-Damaging Therapeutic Drugs.

    Khongkow, Pasarat / Middleton, Anna W / Wong, Jocelyn P-M / Kandola, Navrohit K / Kongsema, Mesayamas / de Moraes, Gabriela Nestal / Gomes, Ana R / Lam, Eric W-F

    Methods in molecular biology (Clifton, N.J.)

    2016  Volume 1395, Page(s) E1

    Language English
    Publishing date 2016-08-04
    Publishing country United States
    Document type Published Erratum
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-3347-1_18
    Database MEDical Literature Analysis and Retrieval System OnLINE

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