2. Academic Validation
  3. Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy

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

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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