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Purity: =99.9%
TIC10 (ONC-201, NSC-350625), an imipridone compound, is a novel, potent, orally bioavailable, brain/BBB penetrant, and stable tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inducer with potential anticancer activity. It was initially developed in the 1970s as an anti-seizure agent which acts by inhibiting Akt and ERK, consequently activating Foxo3a and significantly inducing cell surface TRAIL. TIC10 can inactivate Akt and ERK to induce TRAIL through Foxo3a, possesses superior drug properties: delivery across the blood-brain barrier, superior stability and improved pharmacokinetics. TIC10 is a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10.
| Targets |
Akt; ERK
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|---|---|
| ln Vitro |
In several cancer cell lines, TIC10 induces TRAIL protein localization on the cell surface in a p53-independent manner and increases TRAIL mRNA in a dose-dependent manner. While TIC10 exhibits broad-spectrum anti-tumor activity in vitro and causes TRAIL-sensitive HCT116 p53/p53 cells to exhibit an increase in sub-G1 DNA content indicative of cell death, normal fibroblasts are unaffected by TIC10 at equivalent doses. TIC10 spares healthy fibroblasts while reducing the clonogenic survival of cancer cell lines. Similar to TRAIL-mediated apoptosis, TIC10 increases the proportion of sub-G1 DNA in cancer cells in a p53-independent and Bax-dependent manner. The up-regulation of TRAIL caused by TIC10 is dependent on Foxo3a, which also up-regulates the TRAIL death receptor DR5 and other targets, possibly making some TRAIL-resistant tumor cells susceptible. ERK and Akt kinases are inactivated by TIC10, which causes Foxo3a to move into the nucleus and bind to the TRAIL promoter to activate gene transcription. Foxo3a is then transported into the nucleus. The effective antitumor drug TIC10 works by increasing the levels of the naturally occurring tumor suppressor TRAIL in tumor cells and their surrounding tissue. [1]
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| ln Vivo |
TIC10 and TRAIL treatment causes tumor regression in the HCT116 p53−/− xenograft to a comparable extent when both are administered as multiple doses. TIC10 also induces regression of MDA-MB-231 human triple-negative breast cancer xenografts, whereas TRAIL-treated tumors progressed. In DLD-1 colon cancer xenografts, TIC10 induces tumor stasis one week after treatment, whereas TRAIL-treated tumors advance after a single dose. The SW480 xenograft also exhibits a sustained regression after receiving a single dose of TIC10, and this effect is seen whether the drug is administered orally or intraperitoneally. This suggests that TIC10 has a favorable oral bioavailability. TIC10 causes tumor-specific cell death by TRAIL-mediated direct and bystander effects. TIC10 is an effective antitumor agent against orthotopic human glioblastoma multiforme tumors. [1]
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| Enzyme Assay |
ChIP assays [1]
ChIP assays were carried out as previously described for the TRAIL promoter with a ChIP-grade antibody for Foxo3a or an equivalent concentration of rabbit immunoglobulin G as a nonspecific control. |
| Cell Assay |
Cells were treated with 10 μM ONC201 or DMSO for 24 h.
Colony formation assays [1] The indicated cell lines were plated at 500 cells per well and allowed to adhere, and then treated the next day in fresh complete medium. At 3 days after treatment, the medium was replaced with drug-free medium and cells were propagated for 10 days, with fresh medium given once every 3 days. At the end of the 10-day period, cells were washed in PBS, fixed with methanol, stained with Coomassie blue, rinsed, and dried for quantification. Western blot analysis [1] Western blot analysis was conducted as previously described (41) with NuPAGE 4 to 12% bis-tris gel and visualized with SuperSignal West Femto and x-ray film. Densitometry was performed with NIH ImageJ. Nuclear and cytoplasmic extracts were prepared with a cytoplasmic lysis buffer (10 mM Hepes, 10 mM KCl, 2 mM MgCl2, 1 mM dithiothreitol) followed by a nuclear lysis buffer (20 mM Hepes, 420 mM NaCl, 1.5 mM MgCl2, 250 μM EDTA, 25% glycerol). For all lysis buffers, fresh protease inhibitor and 1 mM sodium orthovanadate were added immediately before use. |
| Animal Protocol |
Female athymic nu/nu mice
25, 50, 100 mg/kg Intraperitoneal/oral All animal experiments were conducted in accordance with the Institutional Animal Care and Use Committee at the Pennsylvania State University College of Medicine. For subcutaneous xenografts, 4- to 6-week-old female athymic nu/nu mice (Charles River Laboratories) were inoculated with 1 × 106 cells (2.5 × 106 for T98G) of the indicated cell lines in each rear flank as a 200-μl suspension of 1:1 Matrigel (BD)/PBS. All subcutaneous tumors were allowed to establish for 1 to 4 weeks after injection until reaching a volume of ~125 mm3 before treatment initiation.[1] |
| References | |
| Additional Infomation |
Dordaviprone (ONC-201) is under investigation in clinical trial NCT03394027 (ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma).
Dordaviprone is a water soluble, orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) and extracellular signal-regulated kinase (ERK), with potential antineoplastic activity. Upon administration, dordaviprone binds to and inhibits the activity of Akt and ERK, which may result in inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway as well as the mitogen-activated protein kinase (MAPK)/ERK-mediated pathway. This may lead to the induction of tumor cell apoptosis mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL death receptor type 5 (DR5) signaling in AKT/ERK-overexpressing tumor cells. The PI3K/Akt signaling pathway and MAPK/ERK pathway are upregulated in a variety of tumor cell types and play a key role in tumor cell proliferation, differentiation and survival by inhibiting apoptosis. In addition, ONC201 is able to cross the blood-brain barrier. |
| Molecular Formula |
C24H26N4O
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|---|---|---|
| Molecular Weight |
386.49
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| Exact Mass |
386.21
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| Elemental Analysis |
C, 74.58; H, 6.78; N, 14.50; O, 4.14
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| CAS # |
1616632-77-9
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| Related CAS # |
41276-02-2 (isomer);1616632-77-9;1638178-82-1 (HCl);1777785-71-3 (HBr);2007141-57-1 (2HBr);
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| PubChem CID |
73777259
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
559.7±60.0 °C at 760 mmHg
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| Flash Point |
292.3±32.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.672
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| LogP |
3.14
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
693
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C2C([H])([H])N(C([H])([H])C3C([H])=C([H])C([H])=C([H])C=3[H])C([H])([H])C([H])([H])C=2N2C([H])([H])C([H])([H])N=C2N1C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1C([H])([H])[H]
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| InChi Key |
RSAQARAFWMUYLL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H26N4O/c1-18-7-5-6-10-20(18)16-28-22-11-13-26(15-19-8-3-2-4-9-19)17-21(22)23(29)27-14-12-25-24(27)28/h2-10H,11-17H2,1H3
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| Chemical Name |
7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5874 mL | 12.9369 mL | 25.8739 mL | |
| 5 mM | 0.5175 mL | 2.5874 mL | 5.1748 mL | |
| 10 mM | 0.2587 mL | 1.2937 mL | 2.5874 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06012929 | Not yet recruiting | Drug: ONC201 | Meningioma Refractory Meningioma |
University of Nebraska | January 2024 | Phase 1 |
| NCT04629209 | Not yet recruiting | Drug: ONC201 | Glioblastoma | Masonic Cancer Center, University of Minnesota |
June 28, 2024 | Phase 2 |
| NCT05630794 | Not yet recruiting | Procedure: Biopsy Drug: Dordaviprone |
Colorectal Carcinoma Colorectal Adenomatous Polyp |
National Cancer Institute (NCI) |
May 13, 2023 | Phase 1 |
| NCT03932643 | Recruiting | Drug: ONC201 | Acute Myeloid Leukemia Myelodysplastic Syndromes |
University of Nebraska | July 30, 2019 | Phase 1 |
| NCT04055649 | Recruiting | Drug: Paclitaxel Drug: Akt/ERK Inhibitor ONC201 |
Malignant Ovarian Epithelial Tumor | Ira Winer | January 21, 2020 | Phase 2 |
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