ONC212
目录号 : GC34095
A GPR132 agonist
Cas No.:1807861-48-8
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
Cell experiment: | All pancreatic cancer cell lines are treated with ONC201 or ONC212 at the indicated doses and time-points. Post-treatment, both floating and adherent cells are collected, fixed in 70% ethanol and stained with propidium iodide in the presence of ribonuclease A. Flow cytometric data is collected using a flow cytometer. The sub-G1 fraction (apoptotic) is quantified, and analysis is performed to quantify the distribution of cells in G1, S and G2-M phases of the cell cycle utilizing[2]. |
Animal experiment: | Six- to seven-week-old female athymic nu/nu mice are used in this study. A total of 3 to 5×106 luciferase-expressing cells are suspended in 50 μL of PBS mixed with 50 μL of Matrigel and subcutaneously injected into the rear flanks of the mice. When tumor volume reaches an average of 100 to 150 cm3, mice are randomly assigned to the indicated control or treatment groups. ONC201 and ONC212 are delivered in a solution of 10% DMSO, 20% Kolliphor®EL and 70% PBS by oral gavage. The length (L) and width (W) of the tumors are measured 1 to 2 times a week using a digital caliper, and the volume of the tumor is calculated. Mice are also weighed once a week to monitor signs of drug toxicity[2]. |
References: [1]. Takenobu Nii, et al. The Novel Imipridone ONC212 Induces Pronounced Anti-Leukemia Effects in Vitro and In Vivo and Is Highly Synergistic with the BCL-2 Inhibitor ABT-199. ASH. 2017. | |
ONC212 is an agonist of the orphan G protein-coupled receptor GPR132 (EC50 = ~400 nM in a PathHunter? β-arrestin assay).1 It inhibits cell growth in a panel of 62 human leukemia cell lines, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and hairy cell leukemias, with GI50 values ranging from less than 78 to 456 nM. ONC212 also reduces cell growth in a panel of 58 lymphoma cell lines (GI50s = <78-261 nM). In vivo, ONC212 (50 mg/kg) reduces tumor volume in HT-29 and HCT116 mouse xenograft models.2
1.Prabhu, V.V., Madhukar, N., Tarapore, R., et al.Abstract 1155: Potent anti-cancer effects of selective GPR132/G2A agonist imipridone ONC212 in leukemia and lymphomaCancer Res.77(13)(2017) 2.Wagner, J., Kline, C.L., Ralff, M.D., et al.Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212Cell Cycle16(19)1790-1799(2017)
| Cas No. | 1807861-48-8 | SDF | |
| Canonical SMILES | O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C3=NCCN3C4=C1CN(CC5=CC=CC=C5)CC4 | ||
| 分子式 | C24H23F3N4O | 分子量 | 440.46 |
| 溶解度 | DMSO : 50 mg/mL (113.52 mM) | 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 | 2.2704 mL | 11.3518 mL | 22.7035 mL |
| 5 mM | 0.4541 mL | 2.2704 mL | 4.5407 mL |
| 10 mM | 0.227 mL | 1.1352 mL | 2.2704 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。
ONC212 is a Novel Mitocan Acting Synergistically with Glycolysis Inhibition in Pancreatic Cancer
Mol Cancer Ther 2021 Sep;20(9):1572-1583.PMID:34224362DOI:10.1158/1535-7163.MCT-20-0962.
ONC212 is a fluorinated imipridone with preclinical efficacy against pancreatic and other malignancies. Although mitochondrial protease ClpP was identified as an ONC212-binding target, the mechanism leading to cancer cell death is incompletely understood. We investigated mitochondrial dysfunction and metabolic rewiring triggered by ONC212 in pancreatic cancer, a deadly malignancy with an urgent need for novel therapeutics. We found ClpP is expressed in pancreatic cancer cells and is required for ONC212 cytotoxicity. ClpX, the regulatory binding partner of ClpP, is suppressed upon ONC212 treatment. Immunoblotting and extracellular flux analysis showed ONC212 impairs oxidative phosphorylation (OXPHOS) with decrease in mitochondrial-derived ATP production. Although collapse of mitochondrial function is observed across ONC212-treated cell lines, only OXPHOS-dependent cells undergo apoptosis. Cells relying on glycolysis undergo growth arrest and upregulate glucose catabolism to prevent ERK1/2 inhibition and apoptosis. Glucose restriction or combination with glycolytic inhibitor 2-deoxy-D-glucose synergize with ONC212 and promote apoptosis in vitro and in vivo Thus, ONC212 is a novel mitocan targeting oxidative metabolism in pancreatic cancer, leading to different cellular outcomes based on divergent metabolic programs.
Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia
Leukemia 2019 Dec;33(12):2805-2816.PMID:31127149DOI:10.1038/s41375-019-0491-z.
Imipridones constitute a novel class of antitumor agents. Here, we report that a second-generation imipridone, ONC212, possesses highly increased antitumor activity compared to the first-generation compound ONC201. In vitro studies using human acute myeloid leukemia (AML) cell lines, primary AML, and normal bone marrow (BM) samples demonstrate that ONC212 exerts prominent apoptogenic effects in AML, but not in normal BM cells, suggesting potential clinical utility. Imipridones putatively engage G protein-coupled receptors (GPCRs) and/or trigger an integrated stress response in hematopoietic tumor cells. Comprehensive GPCR screening identified ONC212 as activator of an orphan GPCR GPR132 and Gαq signaling, which functions as a tumor suppressor. Heterozygous knock-out of GPR132 decreased the antileukemic effects of ONC212. ONC212 induced apoptogenic effects through the induction of an integrated stress response, and reduced MCL-1 expression, a known resistance factor for BCL-2 inhibition by ABT-199. Oral administration of ONC212 inhibited AML growth in vivo and improved overall survival in xenografted mice. Moreover, ONC212 abrogated the engraftment capacity of patient-derived AML cells in an NSG PDX model, suggesting potential eradication of AML initiating cells, and was highly synergistic in combination with ABT-199. Collectively, our results suggest ONC212 as a novel therapeutic agent for AML.
Induction of Synthetic Lethality by Activation of Mitochondrial ClpP and Inhibition of HDAC1/2 in Glioblastoma
Clin Cancer Res 2022 May 2;28(9):1881-1895.PMID:35417530DOI:10.1158/1078-0432.CCR-21-2857.
Purpose: Novel therapeutic targets are critical to unravel for the most common primary brain tumor in adults, glioblastoma (GBM). We have identified a novel synthetic lethal interaction between ClpP activation and HDAC1/2 inhibition that converges on GBM energy metabolism. Experimental design: Transcriptome, metabolite, and U-13C-glucose tracing analyses were utilized in patient-derived xenograft (PDX) models of GBM. Orthotopic GBM models were used for in vivo studies. Results: We showed that activation of the mitochondrial ClpP protease by mutant ClpP (Y118A) or through utilization of second-generation imipridone compounds (ONC206 and ONC212) in combination with genetic interference of HDAC1 and HDAC2 as well as with global (panobinostat) or selective (romidepsin) HDAC inhibitors caused synergistic reduction of viability in GBM model systems, which was mediated by interference with tricarboxylic acid cycle activity and GBM cell respiration. This effect was partially mediated by activation of apoptosis along with activation of caspases regulated chiefly by Bcl-xL and Mcl-1. Knockdown of the ClpP protease or ectopic expression of a ClpP D190A mutant substantially rescued from the inhibition of oxidative energy metabolism as well as from the reduction of cellular viability by ClpP activators and the combination treatment, respectively. Finally, utilizing GBM PDX models, we demonstrated that the combination treatment of HDAC inhibitors and imipridones prolonged host survival more potently than single treatments or vehicle in vivo. Conclusions: Collectively, these observations suggest that the efficacy of HDAC inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.
Targeting mitochondrial respiration for the treatment of acute myeloid leukemia
Biochem Pharmacol 2020 Dec;182:114253.PMID:33011159DOI:10.1016/j.bcp.2020.114253.
Acute myeloid leukemia (AML) is a heterogeneous disease with variable presentation, molecular phenotype, and cytogenetic abnormalities and has seen very little improvement in patient survival over the last few decades. This heterogeneity supports poor prognosis partially through the variability in response to the standard chemotherapy. Further understanding of molecular heterogeneity has promoted the development of novel treatments, some of which target mitochondrial metabolism and function. This review discusses the relative dependency that AML cells have on mitochondrial function, and the ability to pivot this reliance to target important subsets of AML cells, including leukemia stem cells (LSCs). LSCs are tumor-initiating cells that are resistant to standard chemotherapy and promote the persistence and relapse of AML. Historically, LSCs have been targeted based on immunophenotype, but recent developments in the understanding of LSC metabolism has demonstrated unique abilities to target LSCs while sparing normal hematopoietic stem cells (HSCs) through inhibition of mitochondrial function. Here we highlight the use of small molecules that have been demonstrated to effectively target mitochondrial function. IACS-010759 and ME-344 target the electron transport chain (ETC) to inhibit oxidative phosphorylation (OXPHOS). The imipridone family (ONC201, ONC206, ONC212) of inhibitors target mitochondria through activation of ClpP mitochondrial protease and reduce function of essential pathways. These molecules offer a new mechanism for developing clinical therapies in AML and support novel strategies to target LSCs in parallel with conventional therapies.
Targeting Mitochondria in Melanoma
Biomolecules 2020 Sep 30;10(10):1395.PMID:33007949DOI:10.3390/biom10101395.
Drastically elevated glycolytic activity is a prominent metabolic feature of cancer cells. Until recently it was thought that tumor cells shift their entire energy production from oxidative phosphorylation (OXPHOS) to glycolysis. However, new evidence indicates that many cancer cells still have functional OXPHOS, despite their increased reliance on glycolysis. Growing pre-clinical and clinical evidence suggests that targeting mitochondrial metabolism has anti-cancer effects. Here, we analyzed mitochondrial respiration and the amount and activity of OXPHOS complexes in four melanoma cell lines and normal human dermal fibroblasts (HDFs) by Seahorse real-time cell metabolic analysis, immunoblotting, and spectrophotometry. We also tested three clinically approved antibiotics, one anti-parasitic drug (pyrvinium pamoate), and a novel anti-cancer agent (ONC212) for effects on mitochondrial respiration and proliferation of melanoma cells and HDFs. We found that three of the four melanoma cell lines have elevated glycolysis as well as OXPHOS, but contain dysfunctional mitochondria. The antibiotics produced different effects on the melanoma cells and HDFs. The anti-parasitic drug strongly inhibited respiration and proliferation of both the melanoma cells and HDFs. ONC212 reduced respiration in melanoma cells and HDFs, and inhibited the proliferation of melanoma cells. Our findings highlight ONC212 as a promising drug for targeting mitochondrial respiration in cancer.