The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer

John K. Eaton; Priya Chatterji; Laura Furst; Sneha Basak; Ayesha M. Patel; Yan Y. Sweat; Luke L. Cai; Krishna Dave; Rachelle A. Victorio; Elizabeth M. Pizzi; Javad Noorbakhsh; Gaochao Tian; Jennifer A. Roth; John Hynes; Gang Xing; Mathias J. Wawer; Vasanthi S. Viswanathan

doi:10.1101/2024.04.28.591552

Cancer BiologybioRxivApr 28, 2024

Preprint

The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer

John K. Eaton iD, Priya Chatterji iD, Laura Furst, Sneha Basak iD, Ayesha M. Patel iD, Yan Y. Sweat iD, Luke L. Cai iD, Krishna Dave, Rachelle A. Victorio iD, Elizabeth M. Pizzi, Javad Noorbakhsh iD, Gaochao Tian iD, Jennifer A. Roth iD, John Hynes, Gang Xing iD, Mathias J. Wawer iD, Vasanthi S. Viswanathan iD

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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