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Purity: ≥98%
TIC10 Analogue (ONC201 isomer) is an analog/isomer of TIC10 and the 'inactive form' of TIC10. Although it is inactive and did not reduce the viability of cancer cells, it was structurally similar to TIC10. Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces 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 microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.
| Targets |
Akt; ERK
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|---|---|
| ln Vitro |
In several cancer cell lines, TIC10 increases TRAIL mRNA in a dose-dependent manner and induces TRAIL protein localization on the cell surface in a p53-independent 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 do not experience similar changes in their cell cycle profiles. Cancer cell lines' ability to reproduce clonally is reduced by TIC10 while healthy fibroblasts are unaffected. Similar to TRAIL-mediated apoptosis, TIC10 raises the proportion of sub-G1 DNA in cancer cells in a p53-independent and Bax-dependent manner. Foxo3a is required for TIC10-induced TRAIL up-regulation, and it also up-regulates the TRAIL death receptor DR5, among other targets, which may make 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. Additionally, TIC10 causes the MDA-MB-231 human triple-negative breast cancer xenografts to regress, whereas the tumors advanced when TRAIL was administered. TIC10 induces tumor stasis in DLD-1 colon cancer xenografts one week after treatment, whereas TRAIL-treated tumors advance after a single dose. The fact that TIC10 is equally effective when administered orally or intraperitoneally and causes a sustained regression of the SW480 xenograft suggests that TIC10 has a good oral bioavailability. Through direct and indirect effects of TRAIL, TIC10 kills tumor-specific cells. Glioblastoma multiforme tumors in humans that are orthotopic can be effectively treated with TIC10. [1]
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| Enzyme Assay |
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 [1].
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| Cell Assay |
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. TIC10 has broad-spectrum activity against multiple malignancies in vitro and induces an increase in sub-G1 DNA content suggestive of cell death in TRAIL-sensitive HCT116 p53−/− cells, but does not alter the cell cycle profiles of normal fibroblasts at equivalent doses. TIC10 decreases the clonogenic survival of cancer cell lines and spares normal fibroblasts. TIC10 increases the percentage of sub-G1 DNA in cancer cells in a p53-independent and Bax-dependent manner, as previously reported for TRAIL-mediated apoptosis. TIC10-induced TRAIL up-regulation is Foxo3a-dependent, which also up-regulates TRAIL death receptor DR5 among other targets, potentially allowing for sensitization of some TRAIL-resistant tumor cells. 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 microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.
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| Animal Protocol |
Female athymic nu/nu mice
25, 50, 100 mg/kg Intraperitoneal/oral |
| References |
| 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 # |
41276-02-2
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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 |
336423
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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 |
3.19
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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=C(C(C1)=C(N2CC3=C(C)C=CC=C3)CCN1CC4=CC=CC=C4)N5C2=NCC5
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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 |
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| Synonyms |
TIC10 isomer; TIC 10 isomer; TIC10 isomer; ONC201 isomer; ONC 201 isomer; ONC201 isomer
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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) |
DMSO: ~11 mg/mL (28.5 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.5 mg/mL (1.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.5 mg/mL (1.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.5 mg/mL (1.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| 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.
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TIC10 induces TRAIL in tumor and normal cells. |
TIC10 is effective as an antitumor agent in GBM. |
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