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

TitleDiscovery and clinical introduction of first-in-class imipridone ONC201.
Publication TypeJournal Article
Year of Publication2016
AuthorsAllen JE, C Kline LB, Prabhu VV, Wagner J, Ishizawa J, Madhukar N, Lev A, Baumeister M, Zhou L, Lulla A, Stogniew M, Schalop L, Benes C, Kaufman HL, Pottorf RS, B Nallaganchu R, Olson GL, Al-Mulla F, Duvic M, Wu GSheng, Dicker DT, Talekar MK, Lim B, Elemento O, Oster W, Bertino J, Flaherty K, Wang ML, Borthakur G, Andreeff M, Stein M, El-Deiry WS
Date Published2016 Nov 08
KeywordsAnimals, Antineoplastic Agents, Cell Line, Tumor, Heterocyclic Compounds, 4 or More Rings, Humans, Neoplasms

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.

Alternate JournalOncotarget
PubMed ID27602582
PubMed Central IDPMC5342060
Grant ListP50 CA100632 / CA / NCI NIH HHS / United States
R01 CA173453 / CA / NCI NIH HHS / United States
R43 CA177002 / CA / NCI NIH HHS / United States
R01 CA174949 / CA / NCI NIH HHS / United States
P30 CA006927 / CA / NCI NIH HHS / United States