Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction

KM Fujihara; BZ Zhang; TD Jackson; MO Ogunkola; B Nijagal; JV Milne; DA Sallman; CS Ang; I Nikolic; CJ Kearney; SJ Hogg; CS Cabalag; VR Sutton; S Watt; AT Fujihara; JA Trapani; KJ Simpson; D Stojanovski; S Leimkühler; S Haupt; WA Phillips; NJ Clemons

Journal article

Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction

KM Fujihara, BZ Zhang, TD Jackson, MO Ogunkola, B Nijagal, JV Milne, DA Sallman, CS Ang, I Nikolic, CJ Kearney, SJ Hogg, CS Cabalag, VR Sutton, S Watt, AT Fujihara, JA Trapani, KJ Simpson, D Stojanovski, S Leimkühler, S Haupt Show all

Science Advances | Published : 2022

DOI: 10.1126/sciadv.abm9427

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Abstract

The mechanism of action of eprenetapopt (APR-246, PRIMA-1MET) as an anticancer agent remains unresolved, although the clinical development of eprenetapopt focuses on its reported mechanism of action as a mutant-p53 reactivator. Using unbiased approaches, this study demonstrates that eprenetapopt depletes cellular antioxidant glutathione levels by increasing its turnover, triggering a nonapoptotic, iron-dependent form of cell death known as ferroptosis. Deficiency in genes responsible for supplying cancer cells with the substrates for de novo glutathione synthesis (SLC7A11, SHMT2, and MTHFD1L), as well as the enzymes required to synthesize glutathione (GCLC and GCLM), augments the activity of..

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University of Melbourne Researchers

Brunda Nijagal Author

Ching-Seng Ang Author

Conor Kearney Author

Vivien Sutton Author

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A NEW PARADIGM FOR TARGETING MUTANT P53 TUMOURS

Over half of all cancers contain mutations in a gene called TP53, also known as the “guardian of the genome”. Mutation of TP53 provides tumo..

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Funding Acknowledgements

This work was supported by a National Health and Medical Research Council (NHMRC) Project Grant (APP1120293 to W.A.P. and N.J.C.) . N.J.C. is supported by a Fellowship (MCRF16002) from the Department of Health and Human Services acting through the Victorian Cancer Agency Fellowship. K.M.F., T.D.J., and J.V.M. are supported by an Australian Research Training Program (RTP) Scholarships. C.S.C. is the recipient of, and supported by, The Alan & Kate Gibson Research Fellowship, 2018. The Victorian Centre for Functional Genomics (K.J.S.) is funded by the Australian Cancer Research Foundation (ACRF) , Phenomics Australia (PA) through funding from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program, the Peter MacCallum Cancer Centre Foundation, and the University of Melbourne Research Collaborative Infrastructure Program (MCRIP) .