# Eprenetapopt

Source: https://onco.cc/drugs/eprenetapopt/  
OnCo record `eprenetapopt` (Treatment). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Eprenetapopt (APR-246) was a drug meant to refold mutant p53, the most common broken protein in cancer. Its phase 3 in blood cancer failed in 2020.

## Summary

Eprenetapopt (APR-246) is a prodrug of methylene quinuclidinone, proposed to covalently modify mutant p53 and restore wild-type conformation. Phase 2 with azacitidine in TP53-mutant MDS reported ~50% complete remission. The phase 3 (n=154) missed its primary endpoint of complete remission rate in 2020 (33% vs 22%, not significant). Aprea pivoted away. Subsequent studies suggest much of the activity reflected glutathione depletion and oxidative stress rather than p53 refolding.

Lesson: TP53 remains undrugged by direct reactivation; the field moved to mutation-specific correctors (rezatapopt for Y220C) and to exploiting p53-loss dependencies (WEE1, ATR).

## Fields

- Kind: Treatment
- Status: negative
- Last checked: 2026-09-06
- Tags: failure; lesson:wrong-target
- Code: APR-246
- Modality: Small molecule (p53 reactivator)
- Mechanism: Converted to MQ, which alkylates cysteines in mutant p53 (claimed) and depletes glutathione.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Eprenetapopt
- Aprea phase 3 topline (Dec 2020): https://www.globenewswire.com/news-release/2020/12/28/2150865/0/en/Aprea-Therapeutics-Announces-Results-of-Primary-Endpoint-from-Phase-3-Trial-of-Eprenetapopt-in-TP53-Mutant-Myelodysplastic-Syndromes-MDS.html

## Connected records

- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/)
- targets: [TP53](https://onco.cc/targets/tp53/)
- companies: [Aprea Therapeutics](https://onco.cc/companies/aprea-therapeutics/)
- pathways: [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [The p53 network (guardian of the genome)](https://onco.cc/pathways/p53-mdm2-axis/)
- bottlenecks: [Failures are hidden](https://onco.cc/bottlenecks/b-negative-results/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- trials: [p53 Activation in Platinum-Resistant High Grade Serous Ovarian Cancer, a Study of PLD With APR-246](https://onco.cc/trials/nct03268382/)
- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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