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

Allen, Joshua E.; Kline, Christina Leah B.; Prabhu, Varun V.; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel S.; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti R.; Stogniew, Martin; Schalop, Lee; Benes, Cyril H.; Kaufman, Howard L.; Pottorf, Richard S.; Nallaganchu, Bhaskara Rao; Olson, Gary L.; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T.; Talekar, Mala; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith T.; Wang, Michael L.; Borthakur, Gautam; Andreeff, Michael; Stein, Mark N.; El‐Deiry, Wafik S.

doi:10.18632/oncotarget.11814

Cited by 115 publications

(179 citation statements)

References 46 publications

(106 reference statements)

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“…The compound is currently being tested in phase II clinical trials of patients with hematological malignancies and solid tumors (14,15). ONC201 was discovered in a phenotypic screen for compounds that could transcriptionally induce the TNF-related apoptosis inducing ligand ( TRAIL ) gene in colon cancer cells, independent of p53 status (16,17).…”

Section: Preclinical Activity Of Onc201 In Glioblastomamentioning

confidence: 99%

ONC201: a new treatment option being tested clinically for recurrent glioblastoma

et al. 2017

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Glioblastoma is an aggressive central nervous system tumor with a 5-year-survival rate of less than 10%. Patients diagnosed with the disease are treated with surgery, radiation and temozolomide chemotherapy. Despite survival benefits, patients eventually relapse. There is a need for new treatments with improved efficacy. Imipridone ONC201 is a small molecule originally identified as a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound. ONC201 has the unique ability to induce expression of both pro-death ligand TRAIL and its receptor DR5 through engagement of the cellular integrated stress response (ISR) pathway. Arrillaga-Romany et al. report early results from futility analysis of a phase II clinical trial of ONC201 in 17 patients with recurrent or refractory glioblastoma conducted at the Massachusetts General Hospital Cancer Center. The results are promising, as ONC201 shows preliminary signs of efficacy. Further testing of ONC201 in an expansion cohort of patients with glioblastoma is ongoing.

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Section: Preclinical Activity Of Onc201 In Glioblastomamentioning

confidence: 99%

ONC201: a new treatment option being tested clinically for recurrent glioblastoma

et al. 2017

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“…Early results from a Phase I clinical trial in advanced solid tumors demonstrated that ONC201 has a therapeutic PK profile, exceptional safety, induction of pharmacodynamics (PD) markers, and preliminary evidence of efficacy in various types of cancers. 8,9 Given the unique imipridone core, 10 we sought to explore chemical derivates of ONC201 to identify compounds with distinct therapeutic properties. We synthesized ONC201 analogs to identify compounds with distinct therapeutic properties that target ONC201-resistant tumor types or possess distinct signaling properties.…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

et al. 2017

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Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.

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“…ONC201 is a member of a new class of anti-cancer compounds known as the imipridones [1]. ONC201 was originally identified as a p53-independent transcriptional inducer of TNF-related apoptosis inducing ligand (TRAIL) [2,3].…”

Section: Introductionmentioning

confidence: 99%

ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non–Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms

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et al. 2017

Molecular Cancer Therapeutics

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Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer.

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

Cited by 115 publications

References 46 publications

ONC201: a new treatment option being tested clinically for recurrent glioblastoma

ONC201: a new treatment option being tested clinically for recurrent glioblastoma

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non–Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms

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