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Title
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Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy
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Author
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Abstract
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| Ferroptosis is an iron-catalysed, non-apoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we report the synthesis of a more stable and readily soluble series of Fer-1 analogues that potently inhibit ferroptosis. The most promising compounds (37, 38 and 39) showed an improved protection compared to Fer-1 against multi-organ injury in mice. No toxicity was observed in mice after daily injection of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns with the current understanding of the mechanism of action of these compounds. Concludingly, these analogues have superior properties compared to Fer-1, show in vivo efficacy and represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models. |
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Language
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English
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Source (journal)
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Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
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Publication
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Washington, D.C.
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2018
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ISSN
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0022-2623
[print]
1520-4804
[online]
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Volume/pages
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61
:22
(2018)
, p. 10126-10140
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ISI
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000451496300019
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Pubmed ID
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30354101
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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Faculty/Department
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Research group
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Project info
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Research in the field of pathophysiology. Identification, lead optimization and validation of necroptosis inhibitors. Investigating the role of ferroptosis in acute liver injury and multiple sclerosis with newly developed chemical tool compounds. Computational investigations of the catalytic mechanism of Staphylococcus aureus transglycosylase: design and chemical synthesis of novel mechanism-based inhibitors. INFLA-MED - Fundamental research in the pathophysiological processes of inflammatory diseases.
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Publication type
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Subject
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Affiliation
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Publications with a UAntwerp address
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Identification
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Creation
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31.10.2018
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Last edited
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20.09.2021
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To cite this reference
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