(-)-FINO2

(-)-FINO2 is a ferroptosis-inducing peroxide compound that indirectly inhibits glutathione peroxidase 4 (GPX4) and oxidizes iron. It decreases GPX4 activity and protein levels in vitro but does not act as an active site, allosteric, or covalent inhibitor of GPX4 or alter GPX homeostasis. It also oxidizes iron in vitro, leading to degradation of the endoperoxide moiety, but does not affect the protein levels of iron regulatory proteins, such as IRP2, FTL1, or TFR. (-)-FINO2 induces lipid peroxidation of a large subset of the lipidome in HT-1080 cells when used at a concentration of 10 µM and induces ferroptosis in an arachidonic acid lipoxygenase-independent manner. It inhibits cell growth (mean GI50 = 5.8 µM) and induces lethality (mean LC50 = 46 µM) in the NCI-60 panel of cancer cell lines. It is selective for oncogenically transformed BJ-ELR cells over noncancerous BJ-hTERT cells when used at concentrations of 15 and 20 µM. (-)-FINO2 (6 µM) induces oxidative stress, including lipid peroxidation, in RS4;11 B-lymphoblastic leukemia cells. It induces iron-dependent cell death, an effect that can be blocked by pretreatment with the lipophilic antioxidants ferrostatin-1 and liproxstatin-1 , and does not induce markers of apoptosis, necrosis, or autophagy in RS4;11 cells.