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ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

Varun Vijay Prabhu1, Sara Morrow1, Abed Rahman Kawakibi1

  • 1Oncoceutics, Inc., 3675 Market St, Suite 200, Philadelphia, PA 19104, USA.

Neoplasia (New York, N.Y.)
|November 3, 2020
PubMed

Insights

ONC201, a novel imipridone, targets dopamine receptor D2 (DRD2) and mitochondrial caseinolytic protease P (ClpP) to induce cancer cell death. It shows promise in clinical trials for various advanced cancers, including gliomas and lymphomas.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • ONC201, initially identified as TIC10, is a TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound.
  • It exhibits dual activity as a selective antagonist of dopamine receptor D2 (DRD2) and an allosteric agonist of mitochondrial caseinolytic protease P (ClpP).

Purpose of the Study:

  • To elucidate the molecular mechanisms of ONC201's anti-cancer effects.
  • To evaluate its therapeutic potential in various malignancies, including its activity against cancer stem cells and within the tumor microenvironment.

Main Methods:

  • Investigated downstream signaling pathways including the integrated stress response (ATF4/CHOP), oxidative phosphorylation (c-myc), and Akt/ERK signaling.
  • Assessed apoptosis induction via DR5/TRAIL-dependent and independent mechanisms, cell cycle arrest, and antiproliferative effects.
  • Evaluated ONC201's pharmacokinetics, including its ability to cross the blood-brain barrier and its clinical activity in advanced solid tumors and hematological malignancies.

Main Results:

  • ONC201 activates the integrated stress response, leading to DR5/TRAIL-mediated apoptosis, and also induces apoptosis through DR5/TRAIL-independent pathways.
  • It inhibits oxidative phosphorylation and inactivates Akt/ERK signaling, contributing to antiproliferative effects.
  • ONC201 demonstrates single-agent clinical activity in DRD2 and/or ClpP-enriched tumors like high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors.

Conclusions:

  • ONC201 represents a novel therapeutic strategy targeting previously undruggable pathways, including GPCRs, ClpP, and innate immunity.
  • Its ability to affect bulk tumor cells, cancer stem cells, and the tumor microenvironment, coupled with its oral bioavailability and blood-brain barrier penetration, supports its clinical development.
  • Synergistic effects with other cancer therapies are being explored, highlighting the potential of imipridones in oncology.

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