The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer
Eaton, J. K.; Chatterji, P.; Furst, L.; Basak, S.; Patel, A. M.; Sweat, Y. Y.; Cai, L. L.; Dave, K.; Victoria, R. A.; Pizzi, E.; Noorbakhsh, J.; Tian, G.; Roth, J. A. S.; Hynes, J.; Xing, G.; Wawer, M. J.; Viswanathan, V. S.
Show abstract
Despite glutathiones long-recognized role as a major cellular antioxidant and its central role in ferroptosis defense, inhibition of glutathione biosynthetic enzymes has received little attention as a target for the therapeutic induction of ferroptosis. Here, we report that small-molecule inhibition of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis, selectively and potently kills cancer cells by ferroptosis. We further describe novel GCL inhibitors including KOJ-1 and KOJ-2, compounds with excellent cellular potency and pharmacological properties, representing valuable tools to study the biology of ferroptosis and glutathione.
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