Discovery and clinical introduction of first-in-class imipridone ONC201
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Joshua E. Allen1, C. Leah B. Kline2, Varun V. Prabhu1, Jessica Wagner2, Jo Ishizawa3, Neel Madhukar4, Avital Lev2, Marie Baumeister2, Lanlan Zhou2, Amriti Lulla2, Martin Stogniew1, Lee Schalop1, Cyril Benes5,6, Howard L. Kaufman7, Richard S. Pottorf8, B. Rao Nallaganchu8, Gary L. Olson8, Fahd Al-Mulla9, Madeleine Duvic3, Gen Sheng Wu10, David T. Dicker2, Mala K. Talekar11, Bora Lim3, Olivier Elemento4, Wolfgang Oster1, Joseph Bertino7, Keith Flaherty5,6, Michael L. Wang3, Gautam Borthakur3, Michael Andreeff3, Mark Stein7 and Wafik S. El-Deiry2
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
Wafik S. El-Deiry, email:
Keywords: ONC201, TIC10, integrated stress response, ATF4, DRD2
Received: August 23, 2016 Accepted: August 30, 2016 Published: September 01, 2016
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.
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