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Oncotarget. 2016 Nov 8;7(45):74380-74392. doi: 10.18632/oncotarget.11814.

Discovery and clinical introduction of first-in-class imipridone ONC201.

Author information

1
Oncoceutics, Inc., Philadelphia, PA, USA.
2
Fox Chase Cancer Center, Philadelphia, PA, USA.
3
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Weill Cornell Medicine, New York, NY, USA.
5
Massachusetts General Hospital, Boston, MA, USA.
6
Harvard Medical School, Boston, MA, USA.
7
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
8
Provid Pharmaceuticals, Monmouth Junction, NJ, USA.
9
Kuwait University Medical School, Kuwait.
10
Karmanos Cancer Institute, Detroit, MI, USA.
11
The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Abstract

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

KEYWORDS:

ATF4; DRD2; ONC201; TIC10; integrated stress response

PMID:
27602582
PMCID:
PMC5342060
DOI:
10.18632/oncotarget.11814
[Indexed for MEDLINE]
Free PMC Article

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