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

• Published in: Journal of medicinal chemistry Vol. 61; no. 22; pp. 10126 - 10140
• Main Authors: 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, Berghe, Tom Vanden, Augustyns, Koen
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.11.2018; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; MOLECULAR-DYNAMICS; LIPID-PEROXIDATION; GLUTATHIONE-PEROXIDASE 4; VALIDATION; IRON; MECHANISMS; CELL-DEATH
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01299

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.