{"entity":{"id":"eprenetapopt","kind":"drug","name":"Eprenetapopt","aka":[],"tldr":"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.\n\nLesson: TP53 remains undrugged by direct reactivation; the field moved to mutation-specific correctors (rezatapopt for Y220C) and to exploiting p53-loss dependencies (WEE1, ATR).","status":"negative","asOf":"2026-09-06","wikipedia":"https://en.wikipedia.org/wiki/Eprenetapopt","links":[{"label":"Aprea phase 3 topline (Dec 2020)","url":"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"}],"tags":["failure","lesson:wrong-target"],"related":[],"cancers":["aml"],"sections":[],"technologies":[],"targets":["tp53"],"drugs":[],"companies":["aprea-therapeutics"],"institutions":[],"pathways":["p53-cell-cycle"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"code":"APR-246","modality":"Small molecule (p53 reactivator)","mechanism":"Converted to MQ, which alkylates cysteines in mutant p53 (claimed) and depletes glutathione.","approvals":[],"mechanismSteps":[],"toxicity":[],"access":[],"regulatoryEvents":[]},"route":"/drugs/eprenetapopt/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"}],"target":[{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"company":[{"id":"aprea-therapeutics","kind":"company","name":"Aprea Therapeutics","route":"/companies/aprea-therapeutics/"}],"pathway":[{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"p53-mdm2-axis","kind":"pathway","name":"The p53 network (guardian of the genome)","route":"/pathways/p53-mdm2-axis/"}],"bottleneck":[{"id":"b-negative-results","kind":"bottleneck","name":"Failures are hidden","route":"/bottlenecks/b-negative-results/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"trial":[{"id":"nct03268382","kind":"trial","name":"p53 Activation in Platinum-Resistant High Grade Serous Ovarian Cancer, a Study of PLD With APR-246","route":"/trials/nct03268382/"}],"roadmap":[{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","route":"/roadmaps/epigenetics-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}