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

Fujihara, Kenji M.; Zhang, Bonnie Z.; Jackson, Thomas Daniel; Ogunkola, Moses Olalekan; Nijagal, Brunda; Milne, Julia V.; Sallman, David A.; C, Ang; Nikolić, Iva; Kearney, Conor J.; Hogg, Simon J.; Cabalag, Carlos S.; Sutton, Vivien R.; Watt, Sally V.; Fujihara, Asuka T; Trapani, Joseph A.; Simpson, Kaylene J.; Stojanovski, Diana; Leimkühler, Silke; Haupt, Sue; Phillips, Wayne A.; Clemons, Nicholas J.

doi:10.1126/sciadv.abm9427

Cited by 38 publications

(30 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 390 – 396 Tumor cell lines carrying TP53 , TP53 mutations, or TP53 deletions responded to APR-246 treatment. 397 – 400 However, growing evidence suggests that APR-246 exerts its effects through a multitude of pathways independent of p53, 401 – 404 such as downregulating glutathione concentrations in tumor cells, 405 , 406 regulating oxidation-reduction homeostasis 407 – 409 in tumor cells to trigger ferroptosis, 410 – 412 and inducing endoplasmic reticulum stress 413 or unfolded protein responses. 414 …”

Section: Structure-based P53 Targetingmentioning

confidence: 99%

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

153

View full text Add to dashboard Cite

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the “guardian of the genome”. Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an “undruggable” target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.

show abstract

Section: Structure-based P53 Targetingmentioning

confidence: 99%

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

153

View full text Add to dashboard Cite

show abstract

“…The restoration of wild-type TP53 expression triggers cell death by inducing apoptosis in tumor cells [ 112 ]. Eprenetapopt can also induce p53-independent cell death in the course of ferroptosis, a recently described cell death process [ 113 ].…”

Section: In the Grip Of Apoptosis—the Desired Future After Venetoclaxmentioning

confidence: 99%

Targeting Apoptosis in AML: Where Do We Stand?

Krawiec

Strzałka²,

Czemerska³

et al. 2022

Cancers

View full text Add to dashboard Cite

More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies.

show abstract

“…Recent work identified that the small molecule pro-drug eprenetapopt (used interchangeably in our figures as APR-246) promotes ferroptosis in a range of cancer cells [49,50]. Of relevance, ferroptosis is suppressed in the presence of high levels the cystine-glutamate antiporter SLC7A11, which imports cystine across the plasma membrane, feeding the biosynthesis of the antioxidant glutathione.…”

Section: A Cellular Senescencementioning

confidence: 99%

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Mejía-Hernández

Raghu

Caramia

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.

show abstract

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

Cited by 38 publications

References 60 publications

Targeting p53 pathways: mechanisms, structures and advances in therapy

Targeting p53 pathways: mechanisms, structures and advances in therapy

Targeting Apoptosis in AML: Where Do We Stand?

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Contact Info

Product

Resources

About