TIC10Potent Akt/ERK inhibitor CAS# 41276-02-2 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
| Cas No. | 41276-02-2 | SDF | Download SDF |
| PubChem ID | 336423 | Appearance | Powder |
| Formula | C24H26N4O | M.Wt | 386.49 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | ONC201 isomer | ||
| Solubility | DMSO : 5 mg/mL (12.94 mM; Need ultrasonic) | ||
| SMILES | CC1=CC=CC=C1CN2C3=C(CN(CC3)CC4=CC=CC=C4)C(=O)N5C2=NCC5 | ||
| Standard InChIKey | RSAQARAFWMUYLL-UHFFFAOYSA-N | ||
| Standard InChI | 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 | ||
| 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 an inhibitor of Akt and ERK. | |||||
| Targets | Akt | ERK | ||||
TIC10 Dilution Calculator
TIC10 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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TIC10 (TRAIL-inducing compound 10) is a potent and stable small molecule that is orally active. It induces TRAIL transcriptionally independent of p53 and crosses the blood-brain barrier. [1]
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an apoptosis inducer in a variety of human cancer cell lines. It also acts as a tumor suppressor during immune surveillance but the function is lost in cancer progression. [1]
TIC10 caused a prominent and long-lasting production of TRAIL on cell surface of tumor cell.
TIC10 also led to TRAIL-mediated apoptosis in HCT116 p53-/- cells. In addition, TIC10 inactivated Akt and ERK cooperatively lead to the nuclear translocation of Foxo3a and ensuing TRAIL up-regulation. [1]
In mouse caner xenograft, TIC10 showed TRAIL-dependent antitumor effect. It caused tumor-specific cell death by RAIL-mediated direct and bystander effects. TIC10 is also an effective antitumor agent for orthotopic human glioblastoma multiforme tumors. [1]
Reference:
1. Allen JE, Krigsfeld G, Mayes PA et al. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med. 2013 Feb 6;5(171):171ra17.
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TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo.[Pubmed:26474387]
Oncotarget. 2015 Nov 3;6(34):36456-71.
Glioblastoma is the most frequent primary brain tumor in adults. Current therapeutic options are sparse and the prognosis of patients suffering from this disease is grim. Abundance in intratumoral heterogeneity among different deregulated signaling pathways is a hallmark of glioblastoma and likely accounts for its recurrence and resistance to treatment. Glioblastomas harbor a plethora of deregulated pathways driving tumor formation and growth. In this study, we show that TIC10/ONC201, a promising compound that is currently in planned clinical development, along with Bcl-2/Bcl-xL inhibition by ABT263 yields a strong synergistic antiproliferative effect on pediatric, adult, proneural glioblastoma and glioma stem-like cells. On the molecular level, treatment with TIC10/ONC201 results in a posttranslational decrease of the anti-apoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), through modulation of the chaperone Bag3 and the deubiquitinase Usp9X. Consistently, the combination treatment of TIC10/ONC201 and ABT263 required the presence of functional BAX and BAK to drive intrinsic apoptosis, but is surprisingly independent of the extrinsic apoptotic pathway. Moreover, the expression of Noxa protein was required for efficient apoptosis induction by TIC10/ONC201 and ABT263. Importantly, the drug combination of TIC10/ONC201 and the BH3-mimetic, ABT263, led to a regression of tumors in vivo, without any notable toxicity and side effects. Overall, TIC10/ONC201 along with Bcl-2/Bcl-xL inhibition holds significant promise as a novel potential approach for the treatment of recalcitrant tumors such as glioblastoma.
Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.[Pubmed:25927855]
Mol Cancer. 2015 May 1;14:99.
BACKGROUND: We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. METHODS: We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. RESULTS: Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. CONCLUSION: These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.
The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent.[Pubmed:27233611]
Biochem Biophys Res Commun. 2016 Aug 5;476(4):260-266.
Here we evaluated the potential anti-pancreatic cancer activity by TIC10/ONC201, a first-in-class small-molecule inducer of tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL). The in vitro results showed that TIC10 induced potent cytotoxic and cytostatic activities in several human pancreatic cancer cell lines (Panc-1, Mia-PaCa2, AsPC-1 or L3.6). TIC10 activated both extrinsic (TRAIL-caspase-8-dependent) and endogenous/mitochondrial (caspase-9-dependent) apoptosis pathways in the pancreatic cancer cells. Molecularly, we showed that TIC10 inhibited Akt-Erk activation, yet induced TRAIL expression in pancreatic cancer cells. Significantly, TIC10, at a relatively low concentration, sensitized gemcitabine-induced growth inhibition and apoptosis against pancreatic cancer cells. Further, TIC10 and gemcitabine synergistically inhibited Panc-1 xenograft growth in SCID mice. The combination treatment also significantly improved mice survival. In addition, Akt-Erk in-activation and TRAIL/cleaved-caspase-8 induction were observed in TIC10-treated Panc-1 xenografts. Together, the preclinical results of the study demonstrate the potent anti-pancreatic cancer activity by TIC10, or with gemcitabine.
