Discovery and clinical introduction of first-in-class imipridone ONC201
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Author
Allen, Joshua E.
Kline, C. Leah B.
Prabhu, Varun V.
Wagner, Jessica
Ishizawa, Jo
Madhukar, Neel
Lev, Avital
Baumeister, Marie
Zhou, Lanlan
Lulla, Amriti
Stogniew, Martin
Schalop, Lee
Kaufman, Howard L.
Pottorf, Richard S.
Nallaganchu, B. Rao
Olson, Gary L.
Al-Mulla, Fahd
Duvic, Madeleine
Wu, Gen Sheng
Dicker, David T.
Talekar, Mala K.
Lim, Bora
Elemento, Olivier
Oster, Wolfgang
Bertino, Joseph
Wang, Michael L.
Borthakur, Gautam
Andreeff, Michael
Stein, Mark
El-Deiry, Wafik S.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.18632/oncotarget.11814Metadata
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Allen, J. E., C. L. B. Kline, V. V. Prabhu, J. Wagner, J. Ishizawa, N. Madhukar, A. Lev, et al. 2016. “Discovery and clinical introduction of first-in-class imipridone ONC201.” Oncotarget 7 (45): 74380-74392. doi:10.18632/oncotarget.11814. http://dx.doi.org/10.18632/oncotarget.11814.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342060/pdf/Terms of Use
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