bioRxivCancer BiologyPreprint
The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer
John K. EatoniD, Priya ChatterjiiD, Laura Furst, Sneha BasakiD, Ayesha M. PateliD, Yan Y. SweatiD, Luke L. CaiiD, Krishna Dave, Rachelle A. VictorioiD, Elizabeth M. Pizzi, Javad NoorbakhshiD, Gaochao TianiD, Jennifer A. RothiD, John Hynes, Gang XingiD, Mathias J. WaweriD, Vasanthi S. ViswanathaniD
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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