(1S,3R)-RSL3

(1S,3R)-RSL3 is a ferroptosis inducer and is canonically known as an inhibitor of glutathione peroxidase 4 (GPX4).{29243,33037,30722} It inhibits GPX4 in a context-dependent manner: (1S,3R)-RSL3 inhibits GPX4 in the presence of cell cytosol or recombinant human 14-3-3?, an adaptor protein, but does not inhibit recombinant human selenocysteine-containing GPX4 or purified rat testis GPX4, when used at a concentration of 100 µM.{64989,49739} (1S,3R)-RSL3 (50 nM) inhibits peroxidase activity in GPX4-overexpressing COH-BR1 breast cancer cell lysates.{29243} It also inhibits thioredoxin reductase 1 (TrxR1; IC50 = 7.9 µM in a cell-free assay).{64989} (1S,3R)-RSL3 is selectively cytotoxic to H-RasV12-expressing BJeLR cells over wild-type Ras-expressing BJeH cells (EC50s = 0.01 and 2 µM, respectively) and induces lipid peroxidation, a hallmark of ferroptosis, in Pfa1 fibroblasts when used at a concentration of 100 nM.{29243,33037} In vivo, (1S,3R)-RSL3 (100 mg/kg) prevents tumor formation and inhibits tumor growth in BJeLR mouse xenograft models.{29243}