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Related Experiment Video

Updated: May 28, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Integrated Phenotypic and Transcriptomic Profiling Positions ONC212 as a Lead Imipridone in Androgen-Independent

Fatima Ghamlouche1, Amani Yehya1, Abdallah Kurdi2

  • 1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.

International Journal of Molecular Sciences
|May 27, 2026
PubMed
Summary

ONC212, a novel imipridone, shows potent efficacy against advanced prostate cancer stem cells (PCSCs) by inhibiting tumor growth and enhancing stress responses. This derivative demonstrates superior antitumor activity compared to its predecessors in preclinical models.

Keywords:
3D cultureONC206ONC212imipridonesintegrated stress responseprostate cancerprostate cancer stem cellstranscriptomicsunfolded protein response

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Advanced prostate cancer (PCa) is lethal due to stem-like cells (PCSCs) driving tumor growth and resistance.
  • Imipridones are anticancer agents; ONC206 and ONC212 are next-generation derivatives with enhanced potency.
  • Understanding their efficacy in androgen-independent PCa (AIPC) models is crucial for therapeutic development.

Purpose of the Study:

  • To compare the antitumor efficacy and mechanisms of imipridone derivatives ONC201, ONC206, and ONC212.
  • To evaluate their effects on both bulk AIPC cells and PCSCs in 2D and 3D models.
  • To elucidate the molecular pathways modulated by these compounds.

Main Methods:

  • Treatment of DU145 and PC3 AIPC cells with ONC201, ONC206, or ONC212.
  • Functional assays: proliferation, viability, migration, invasion, spheroid formation, cell cycle, mitochondrial potential/mass.
  • RNA sequencing for transcriptional response analysis.

Main Results:

  • ONC212 demonstrated superior potency, inhibiting proliferation, migration, and spheroid formation at nanomolar concentrations.
  • Transcriptomic analysis revealed shared repression of DNA replication and cell cycle, with activation of integrated stress response (ISR/UPR) and FOXO signaling.
  • ONC206 induced apoptosis via PERK-ATF4, while ONC212 impacted oxidative phosphorylation and mitochondrial RNA processing.

Conclusions:

  • ONC212 is a promising imipridone candidate for advanced prostate cancer.
  • It effectively inhibits tumor and PCSC functions through a distinct stress-response signature.
  • Further translational evaluation of ONC212 is warranted.