FA16

FA16 is a ferroptosis inducer and an inhibitor of the system x_c^- cystine/glutamate transporter.¹ It reduces the viability of various cancer cell lines, including HT-1080 fibrosarcoma and A375 melanoma cells (IC₅₀s = 1.26 and 2.31 µM, respectively), 786-O renal cell carcinoma cells (IC₅₀ = 0.7 µM), and MDA-MB-231 breast cancer cells (IC₅₀ = 4.34 µM) but not several non-cancer cell lines at 20 µM. FA16-induced death of HT-1080 cells can be blocked by the ferroptosis inhibitors ferrostatin-1 (Item No. 17729), Trolox (Item No. 10011659), and deferoxamine (DFO; Item No. 14595) and potentiated by ferric ammonium citrate or ferric citrate. FA16-induced death of HT-1080 cells can also be blocked by β-mercaptoethanol, which prevents cell death induced by system x_c^- cystine/glutamate transporter inhibition by increasing intracellular cystine bioavailability. FA16 (5 µM) increases the production of reactive oxygen species (ROS) in HT-1080 cells, an effect that can be blocked by ferrostatin-1, and inhibits glutamate release from HT-1080 cells in an enzyme-coupled glutamate release assay. FA16 (15 and 30 mg/kg) reduces tumor growth and increases intratumoral levels of 4-hydroxy nonenal (4-HNE; Item No. 32100) and malondialdehyde (MDA), markers of lipid peroxidation, in a HepG2 mouse xenograft model. It also has an increased half-life and slower clearance than the ferroptosis inducer erastin (Item No. 17754) in human and rat liver microsomes.

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1. Fang, Y., Tan, Q., Zhou, H., et al. Discovery and optimization of 2-(trifluoromethyl)benzimidazole derivatives as novel ferroptosis inducers in vitro and in vivo. Eur. J. Med. Chem. 245(Pt 1), 114905 (2023).