ONC201
(Synonyms: TIC10) 目录号 : GC11711
A TRAIL-inducing compound
Cas No.:1616632-77-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Cell experiment: |
Floating and adherent cells are analyzed on a Coulter-Beckman Elite Epics cytometer. For surface TRAIL experiments, adherent cells are harvested by brief trypsinization, fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) for 20 min, incubated with an anti-TRAIL antibody at 1:250 overnight, washed and incubated with anti-rabbit Alexa Fluor 488 for 30 min, and analyzed. Cells are gated on forward and side scatter to eliminate debris and dead cells from the analysis. Surface TRAIL data are expressed as median fluorescence intensity relative to that of control samples unless indicated otherwise. Surface DR5 is analyzed similarly with an antibody from Imgenex. For sub-G1content and cell cycle profile analysis, all cells are pelleted and ethanol-fixed, followed by staining with propidium iodide in the presence of RNase. Cell viability assays are carried out in 96-well black-walled clear-bottom plates with CellTiter-Glo[1]. |
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Animal experiment: |
Mice[1] For subcutaneous xenografts, 4- to 6-week-old female athymic nu/nu mice are 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 are allowed to establish for 1 to 4 weeks after injection until reaching a volume of ~125 mm3 before treatment initiation. All intraperitoneal and intravenous injections are given at a total volume of 200 μL. Oral formulations of TIC10 are administered by oral gavage and given as a 200 μL suspension containing 20% Cremophor EL, 10% DMSO, and 70% PBS. Tumors are monitored with digital calipers at indicated time points. All subcutaneous tumors are allowed to establish for 1-4 weeks post-injection until reaching a volume of ~125 mm3 before treatment initiation. Relief of tumor burden is monitored for 3 weeks after disappearance of the tumor and confirmed by visual inspection after euthanasia. |
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References: [1]. Allen JE, 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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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).
| Cas No. | 1616632-77-9 | SDF | |
| 别名 | TIC10 | ||
| 化学名 | 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one | ||
| Canonical SMILES | CC1=CC=CC=C1CN(C2=NCCN32)C(C(C4)=C3CCN4CC5=CC=CC=C5)=O | ||
| 分子式 | C24H26N4O | 分子量 | 386.49 |
| 溶解度 | DMSO : ≥100 mg/mL ；Water : Insoluble | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。