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  1. Article: β-D-Arabinosyl 1-C-sulfonic acid

    Won, Walter S / Knapp, Spencer

    Journal of sulphur chemistry

    2012  Volume 34, Issue 1-2, Page(s) 33–37

    Abstract: A short synthetic route to β,d-arabinofuranosyl 1-C-sulfonic acid ( ...

    Abstract A short synthetic route to β,d-arabinofuranosyl 1-C-sulfonic acid (
    Language English
    Publishing date 2012-08-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2142404-4
    ISSN 1741-6000 ; 1741-5993
    ISSN (online) 1741-6000
    ISSN 1741-5993
    DOI 10.1080/17415993.2012.706814
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.

    Ullman, Julie C / Mellem, Kevin T / Xi, Yannan / Ramanan, Vyas / Merritt, Hanne / Choy, Rebeca / Gujral, Tarunmeet / Young, Lyndsay E A / Blake, Kerrigan / Tep, Samnang / Homburger, Julian R / O'Regan, Adam / Ganesh, Sandya / Wong, Perryn / Satterfield, Terrence F / Lin, Baiwei / Situ, Eva / Yu, Cecile / Espanol, Bryan /
    Sarwaikar, Richa / Fastman, Nathan / Tzitzilonis, Christos / Lee, Patrick / Reiton, Daniel / Morton, Vivian / Santiago, Pam / Won, Walter / Powers, Hannah / Cummings, Beryl B / Hoek, Maarten / Graham, Robert R / Chandriani, Sanjay J / Bainer, Russell / DePaoli-Roach, Anna A / Roach, Peter J / Hurley, Thomas D / Sun, Ramon C / Gentry, Matthew S / Sinz, Christopher / Dick, Ryan A / Noonberg, Sarah B / Beattie, David T / Morgans, David J / Green, Eric M

    Science translational medicine

    2024  Volume 16, Issue 730, Page(s) eadf1691

    Abstract: Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are ...

    Abstract Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.
    MeSH term(s) Mice ; Animals ; Glycogen Storage Disease Type II/drug therapy ; Glycogen Synthase/metabolism ; Glycogen Synthase/pharmacology ; Mice, Knockout ; Glycogen/metabolism ; Muscle, Skeletal/metabolism ; Enzyme Replacement Therapy/methods
    Chemical Substances Glycogen Synthase (EC 2.4.1.11) ; Glycogen (9005-79-2)
    Language English
    Publishing date 2024-01-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.adf1691
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6941: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.

    Burnett, G Leslie / Yang, Yu C / Aggen, James B / Pitzen, Jennifer / Gliedt, Micah K / Semko, Chris M / Marquez, Abby / Evans, James W / Wang, Gang / Won, Walter S / Tomlinson, Aidan C A / Kiss, Gert / Tzitzilonis, Christos / Thottumkara, Arun P / Cregg, James / Mellem, Kevin T / Choi, Jong S / Lee, Julie C / Zhao, Yongyuan /
    Lee, Bianca J / Meyerowitz, Justin G / Knox, John E / Jiang, Jingjing / Wang, Zhican / Wildes, David / Wang, Zhengping / Singh, Mallika / Smith, Jacqueline A M / Gill, Adrian L

    Journal of medicinal chemistry

    2022  Volume 66, Issue 1, Page(s) 149–169

    Abstract: Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 ...

    Abstract Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS
    MeSH term(s) Humans ; Mechanistic Target of Rapamycin Complex 1 ; Proto-Oncogene Proteins p21(ras)/metabolism ; Cell Proliferation ; TOR Serine-Threonine Kinases ; Mechanistic Target of Rapamycin Complex 2 ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Lung Neoplasms/drug therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein Kinase Inhibitors/chemistry ; Cell Line, Tumor
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Protein Kinase Inhibitors
    Language English
    Publishing date 2022-12-19
    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.2c01658
    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:
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    ab Jg. 2022: Lesesaal (EG)
    Zs.MB 1: Show issues

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