Abstract
Ferroptosis is implicated in diverse human diseases. Ferroptosis inducers hold great potential for cancer therapy. The existing ferroptosis inducers, however, lack structural diversity, and only a few of them are suitable for in vivo applications. Herein, by phenotypic screenings, we discovered a new ferroptosis inducer FA-S, a 2-(trifluoromethyl)benzimidazole derivative, from which a series of its analogs were designed and synthesized to improve the activity. This produced the most potent compound FA16 with single-digit micromolar activity of ferroptosis induction and satisfactory metabolic stability. Further studies demonstrated that FA16 induced ferroptosis by inhibiting cystine/glutamate antiporter (system Xc−). It is noteworthy that analogue FA16 has more favorable metabolic stability than the classic system Xc− inhibitor erastin, which is not suitable for in vivo studies. FA16 significantly inhibited tumor growth in the HepG2 xenograft model by inducing ferroptosis. This work provides new ferroptosis inducers with a novel scaffold, but also a promising lead for hepatocellular carcinoma treatment. Our work reveals a suitable in vivo ferroptosis-inducing tool to explore the mechanisms underlying ferroptosis and the relevance of ferroptosis to pathogenesis of human diseases.
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