Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy

  • J Med Chem. 2018 Nov 21;61(22):10126-10140. doi: 10.1021/acs.jmedchem.8b01299.
Lars Devisscher  1 ,  Samya Van Coillie  2  3 ,  Sam Hofmans  1 ,  Dries Van Rompaey  1 ,  Kenneth Goossens  1 ,  Eline Meul  2  3 ,  Louis Maes  4 ,  Hans De Winter  1 ,  Pieter Van Der Veken  1 ,  Peter Vandenabeele  2  3  5 ,  Tom Vanden Berghe  2  3 ,  Koen Augustyns  1
Affiliations
  • 1. Laboratory of Medicinal Chemistry , University of Antwerp , Universiteitsplein 1 , 2610 Antwerp , Belgium.
  • 2. Molecular Signalling and Cell Death Unit , VIB Center for Inflammation Research , Technologiepark 927 , 9052 Ghent , Belgium.
  • 3. Department of Biomedical Molecular Biology , Ghent University , 9000 Ghent , Belgium.
  • 4. Laboratory for Microbiology, Parasitology and Hygiene , University of Antwerp , Universiteitsplein 1 , 2610 Antwerp , Belgium.
  • 5. Methusalem Program , Ghent University , 9000 Ghent , Belgium.
PMID: 30354101 DOI: 10.1021/acs.jmedchem.8b01299
Abstract

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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