ONC201
(Synonyms: TIC10) 目录号 : GC11711
ONC201是一种具有口服活性的小分子化合物，属于imipridone类化合物，是多巴胺D2/3受体（DRD2/3）的选择性拮抗剂。
Cas No.:1616632-77-9
Sample solution is provided at 25 µL, 10mM.
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ONC201 is an orally active small molecule compound belonging to the imipridone class and acts as a selective antagonist of the dopamine D2/3 receptors (DRD2/3)[1]. DRD2/3, which are G protein-coupled receptors (GPCRs), are overexpressed in various tumor cells[2]. ONC201 induces tumor cell apoptosis by antagonizing DRD2/3 and activating the ClpP protease, and further enhances its antitumor effects by activating the immune system. This multi-target mechanism of action enables ONC201 to exhibit extensive anti-tumor activity in various tumor types[3]. ONC201 is commonly used in cancer research, particularly in the study of various solid tumors and hematological malignancies[4][5].
In vitro,ONC201 (5μM, 72h) exposure causes a dose-dependent increase in TRAIL mRNA and induces TRAIL protein localization on the cell surface of HCT116 human colon cancer cells in a p53-independent manner, while also inducing TRAIL-mediated apoptosis[6]. Combination of L_GEM and ONC201(200nM,72h) arrests MIA PaCa-2 cells in the G2 phase and induces apoptosis[7].
In vivo, combinated treatment of ONC201(15mg/kg; three times a week for two weeks) and L_GEM reduced the tumor size, inhibited the expression of p-ERK and p-AKT and upregulated the expression of cleaved Caspase 3 of tumor tissues in KPC tumor-bearing syngeneic mice[7].
References:
[1] Stein, M. N., Bertino, J. R., Kaufman, H. L., Mayer, T., Moss, R., Silk, A., Chan, N., Malhotra, J., Rodriguez, L., Aisner, J., Aiken, R. D., Haffty, B. G., DiPaola, R. S., Saunders, T., Zloza, A., Damare, S., Beckett, Y., Yu, B., Najmi, S., Gabel, C., … Mehnert, J. M. (2017). First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 23(15), 4163–4169.
[2] Bonner, E. R., Waszak, S. M., Grotzer, M. A., Mueller, S., & Nazarian, J. (2021). Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro-oncology, 23(4), 542–556.
[3] Prabhu, V. V., Morrow, S., Rahman Kawakibi, A., Zhou, L., Ralff, M., Ray, J., Jhaveri, A., Ferrarini, I., Lee, Y., Parker, C., Zhang, Y., Borsuk, R., Chang, W. I., Honeyman, J. N., Tavora, F., Carneiro, B., Raufi, A., Huntington, K., Carlsen, L., Louie, A., … El-Deiry, W. S. (2020). ONC201 and imipridones: Anti-cancer compounds with clinical efficacy. Neoplasia (New York, N.Y.), 22(12), 725–744.
[4] Allen, J. E., Prabhu, V. V., Talekar, M., van den Heuvel, A. P., Lim, B., Dicker, D. T., Fritz, J. L., Beck, A., & El-Deiry, W. S. (2015). Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10. Cancer research, 75(8), 1668–1674.
[5] Ishizawa, J., Kojima, K., Chachad, D., Ruvolo, P., Ruvolo, V., Jacamo, R. O., Borthakur, G., Mu, H., Zeng, Z., Tabe, Y., Allen, J. E., Wang, Z., Ma, W., Lee, H. C., Orlowski, R., Sarbassov, dosD., Lorenzi, P. L., Huang, X., Neelapu, S. S., McDonnell, T., … Andreeff, M. (2016). ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Science signaling, 9(415), ra17.
[6] Allen, J. E., Krigsfeld, G., Mayes, P. A., Patel, L., Dicker, D. T., Patel, A. S., Dolloff, N. G., Messaris, E., Scata, K. A., Wang, W., Zhou, J. Y., Wu, G. S., & El-Deiry, W. S. (2013). Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Science translational medicine, 5(171), 171ra17.
[7] Kumar, V., Sethi, B., Staller, D. W., Shrestha, P., & Mahato, R. I. (2024). Gemcitabine elaidate and ONC201 combination therapy for inhibiting pancreatic cancer in a KRAS mutated syngeneic mouse model. Cell death discovery, 10(1), 158.
ONC201是一种具有口服活性的小分子化合物，属于imipridone类化合物，是多巴胺D2/3受体（DRD2/3）的选择性拮抗剂[1]。DRD2/3是G蛋白偶联受体（GPCR），在多种肿瘤细胞中过表达[2]。ONC201通过拮抗DRD2/3和激活ClpP蛋白酶诱导肿瘤细胞凋亡，并通过激活免疫系统进一步增强抗肿瘤效果, 这种多靶点作用机制使ONC201在多种肿瘤类型中表现出广泛的抗肿瘤活性[3]。ONC201通常用于癌症研究，特别是针对多种实体瘤和血液系统恶性肿瘤的研究[4][5]。
体外实验中，ONC201（5μM，72小时）处理导致HCT116人结肠癌细胞中TRAIL mRNA的含量呈剂量依赖性增加，并以不依赖p53的方式诱导TRAIL蛋白在细胞表面的定位，同时还诱导TRAIL介导的凋亡[6]。ONC201（200nM，72小时）与L_GEM的联合处理使MIA PaCa-2细胞停滞在G2期，并诱导凋亡[7]。
体内实验中，ONC201（15mg/kg，每周三次，持续两周）与L_GEM的联合治疗在KPC肿瘤小鼠模型中减少了肿瘤大小，抑制了肿瘤组织中p-ERK和p-AKT的表达，并上调了cleaved Caspase 3的表达[7]。
| Cell experiment [1]: | |
Cell lines | HCT116 human colon cancer cells |
Preparation Method | HCT116 human colon cancer cells were treated with or without 5μM ONC201 for 72h, floating and adherent cells were analyzed on a cytometer. For surface TRAIL experiments, adherent cells were 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 were 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 was analyzed similarly with an antibody. For sub-G1 content and cell cycle profile analysis, all cells were pelleted and ethanol-fixed, followed by staining with propidium iodide in the presence of RNase. Cell viability assays were carried out in 96-well black-walled clear-bottom plates with CellTiter-Glo according to the manufacturer’s protocols. |
Reaction Conditions | 5μM; 72h |
Applications | ONC201 exposure causes a dose-dependent increase in TRAIL mRNA and induces TRAIL protein localization on the cell surface of HCT116 human colon cancer cells in a p53-independent manner, while also inducing TRAIL-mediated apoptosis. |
| Animal experiment [2]: | |
Animal models | C57Bl/6J mice |
Preparation Method | Under brief anesthesia, male or female C57Bl/6J mice were injected with freshly harvested KPC tumor pieces (2-3mm) subcutaneously into the right hind flank. Volumes of outgrowing tumors were evaluated using the formula: volume = width2 × length × ½. When tumors reached a volume of approximately 100mm3 , about 9–12 days post-tumor inoculation, animals were injected intravenously (i.v.) with equivalent volumes of solvent alone and served as vehicle-treated controls (vehicle, n=5). Additional groups were injected with L_GEM (20mg/kg), ONC201 (15mg/kg), or their combination three times a week for two weeks. During the treatment, mice were monitored for body weight and tumor volume. Tumor volumes were measured on alternate days and plotted over time. Mice were sacrificed after the treatment regimen or when they became moribund before the tumor volume reached 2000mm3. At the end of each experiment, blood samples, tumors, and other major organs were removed from the animals of all groups for further analysis. |
Dosage form | 15mg/kg; three times a week for two weeks; i.v. |
Applications | Combinated treatment of ONC201and L_GEM reduced the tumor size, inhibited the expression of p-ERK and p-AKT and upregulated the expression of cleaved Caspase 3 of tumor tissues in KPC tumor-bearing syngeneic mice. |
References: | |
| 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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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 |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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