ONC201activates p53-independent apoptosis CAS# 1616632-77-9 |
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Quality Control & MSDS
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| Cas No. | 1616632-77-9 | SDF | Download SDF |
| PubChem ID | 73777259 | Appearance | Powder |
| Formula | C24H26N4O | M.Wt | 386.49 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | ONC-201 | ||
| Solubility | DMSO : 31.25 mg/mL (80.86 mM; Need ultrasonic) | ||
| SMILES | CC1=CC=CC=C1CN2C(=O)C3=C(CCN(C3)CC4=CC=CC=C4)N5C2=NCC5 | ||
| Standard InChIKey | VLULRUCCHYVXOH-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C24H26N4O/c1-18-7-5-6-10-20(18)16-28-23(29)21-17-26(15-19-8-3-2-4-9-19)13-11-22(21)27-14-12-25-24(27)28/h2-10H,11-17H2,1H3 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | TIC10 is a potent, orally active, and stable TRAIL inducer, also inhibits Akt and ERK activity.In Vitro:TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their micro-environment to enhance the concentrations of the endogenous tumor suppressor TRAIL. TIC10 as a TRAIL-inducing compound. TIC10 causes a dose-dependent increase in TRAIL mRNA and induces TRAIL protein localization on the cell surface of several cancer cell lines in a p53-independent manner. Besides, both pAkt and pERK are down-regulated by TIC10 treatment in a dose-dependent manner. TIC10 also causes a down-regulation of the total expression of ERK[1].In Vivo:In DLD-1 colon cancer xenografts, TIC10 induces tumor stasis at 1 week after treatment, whereas TRAIL-treated tumors progress after a single dose. A single dose of TIC10 also induces a sustained regression of the SW480 xenograft and is equally effective when delivered by intraperitoneal or oral route, suggesting favorable oral bioavailability for TIC10. Titration of a single oral dose of TIC10 in the HCT116 xenograft model reveals sustained antitumor efficacy at 25 mg/kg. Exposure to oral TIC10 at 25 mg/kg weekly for 4 weeks in immunocompetent mice does not cause any changes in selected serum chemistry markers. The same oral dosing schedule is applied to Eμ-myc transgenic mice, which spontaneously develop meta-static lymphoma from weeks 9 to 12 of age, and TIC10 significantly (P=0.00789) prolongs the survival of these mice by 4 weeks[1]. References: | |||||
ONC201 Dilution Calculator
ONC201 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.5874 mL | 12.9369 mL | 25.8739 mL | 51.7478 mL | 64.6847 mL |
| 5 mM | 0.5175 mL | 2.5874 mL | 5.1748 mL | 10.3496 mL | 12.9369 mL |
| 10 mM | 0.2587 mL | 1.2937 mL | 2.5874 mL | 5.1748 mL | 6.4685 mL |
| 50 mM | 0.0517 mL | 0.2587 mL | 0.5175 mL | 1.035 mL | 1.2937 mL |
| 100 mM | 0.0259 mL | 0.1294 mL | 0.2587 mL | 0.5175 mL | 0.6468 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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ONC201 is a first-in-class small chemical that activates p53-independent apoptosis with IC50 value less than 2.5 μM in lymphoma and leukemia cells. [1]
ONC201 induced apoptosis in stem and progenitor AML cells and abolish the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 induced changes in gene expression similar to those induced by the unfolded protein response (UPR) and integrated stress responses (ISRs). ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2a. ONC201 also forbid mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. [1]
In solid tumors, ONC201 caused late-stage induction of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) and promoted the transcription of TRAIL gene. ONC201 has substantial antitumor activity in preclinical models in various advanced solid tumors with infrequent oral dosing and without toxicity in normal cells in culture and in vivo [2]. Preclinical studies demonstrated broad synergism of ONC201 with established anticancer therapies, including the depletion of colorectal cancer stem cells [3].
ONC201 induced p53-independent apoptosis and cell cycle arrest in acute myeloid leukemia (AML) and mantle cell lymphoma (MCL) samples from patients; these embraced samples from patients with genetic abnormalities associated with poor prognosis or cells that had produced resistance to the nongenotoxic drugs ibrutinib and bortezomib. [1]
References:
1.ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.Sci Signal. 2016 Feb 16;9(415):ra17.
2.Dual in activation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci. Transl. Med. 5, 171ra117 (2013).
3.Genetic and pharmacological screens converge in identifying FLIP, BCL2 and IAP proteins as key regulators of sensitivity to the TRAIL-inducing anti-cancer agent ONC201/TIC10. Cancer Res. 75, 1668–1674 (2015).
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Discovery and clinical introduction of first-in-class imipridone ONC201.[Pubmed:27602582]
Oncotarget. 2016 Nov 8;7(45):74380-74392.
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.
mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.[Pubmed:27565731]
Biochem Biophys Res Commun. 2016 Sep 30;478(4):1515-20.
We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells.
Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.[Pubmed:27626799]
PLoS One. 2016 Sep 14;11(9):e0162133.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.
First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors.[Pubmed:28331050]
Clin Cancer Res. 2017 Aug 1;23(15):4163-4169.
Purpose: ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D).Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information.Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 mug/mL ( approximately 3.9-19.4 mumol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h.mug/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients.Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163-9. (c)2017 AACR.
