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Targeting Necrosis: Elastase-like Protease Inhibitors Curtail Necrotic Cell Death Both In Vitro and in Three In Vivo Disease Models
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    Targeting Necrosis: Elastase-like Protease Inhibitors Curtail Necrotic Cell Death Both In Vitro and in Three In Vivo Disease Models
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    • Boris Khalfin
      Boris Khalfin
      Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
    • Alexandra Lichtenstein
      Alexandra Lichtenstein
      Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
    • Amnon Albeck*
      Amnon Albeck
      The Julius Spokojny Bioorganic Chemistry Laboratory, Bar Ilan University, Ramat Gan 5290002, Israel
      *Email: [email protected]
      More by Amnon Albeck
    • Ilana Nathan*
      Ilana Nathan
      Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
      Soroka University Medical Center, Beer Sheva 8457108, Israel
      *Email: [email protected]
      More by Ilana Nathan
    Other Access OptionsSupporting Information (2)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 3, 1510–1523
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    https://doi.org/10.1021/acs.jmedchem.0c01683
    Published January 31, 2021
    Copyright © 2021 American Chemical Society

    Abstract

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    Necrosis is the main mode of cell death, which leads to multiple clinical conditions affecting hundreds of millions of people worldwide. Its molecular mechanisms are poorly understood, hampering therapeutics development. Here, we identify key proteolytic activities essential for necrosis using various biochemical approaches, enzymatic assays, medicinal chemistry, and siRNA library screening. These findings provide strategies to treat and prevent necrosis, including known medicines used for other indications, siRNAs, and establish a platform for the design of new inhibitory molecules. Indeed, inhibitors of these pathways demonstrated protective activity in vitro and in vivo in animal models of traumatic brain injury, acute myocardial infarction, and drug-induced liver toxicity. Consequently, this study may pave the way for the development of novel therapies for the treatment, inhibition, or prevention of a large number of hitherto untreatable diseases.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01683.

    • Inhibitors’ purity data, 1H NMR data, and LC–MS data (PDF)

    • Molecular formula strings (SMILES) (CSV)

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    Cited By

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    This article is cited by 1 publications.

    1. Xing Chen, Yan Lou, Feilong Zhou, Daxing Shi, Xinhua Liu, Fangbiao Tao. Identification of novel indolinone derivatives as CTSC inhibitors to treat inflammatory bowel disease by modulating inflammatory factors. European Journal of Medicinal Chemistry 2024, 280 , 116914. https://doi.org/10.1016/j.ejmech.2024.116914

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 3, 1510–1523
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.0c01683
    Published January 31, 2021
    Copyright © 2021 American Chemical Society

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