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Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy

  • Devisscher, Lars
  • Van Coillie, Samya
  • Hofmans, Sam
  • Van Rompaey, Dries
  • Goossens, Kenneth
  • Meul, Eline
  • Maes, Louis
  • De Winter, Hans
  • Van Der Veken, Pieter
  • Vandenabeele, Peter
  • Vanden Berghe, Tom
  • Augustyns, Koen
Publication Date
Jan 01, 2018
Ghent University Institutional Archive
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Ferroptosis is an iron-catalyzed, nonapoptotic 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 multiorgan 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. In conclusion, 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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