ETC-206
(Synonyms: 4-[6-[4-(4-吗啉基羰基)苯基]咪唑并[1,2-A]吡啶-3-基]苄腈) 目录号 : GC33033
An inhibitor of MKNK1 and MKNK2
Cas No.:1464151-33-4
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: | The anti-proliferative effects of ETC-206 are assessed in vitro, using CellTiter-Glo viability assay against 25 hematological cancer cell lines including the K562 cell line that overexpresses eIF4E (K562 o/e eIF4E). The IC50s are in general in the micromolar range[1]. |
Animal experiment: | Mice[1]CD-1 female mice (6-8 weeks old) are weighed, and those selected for dosing are 24±2 g. Three mice are randomly grouped per time point. Mice are administered a single dose of 1 mg/kg of ETC-206 via tail vein injection or a single dose of 5 mg/kg of ETC-206 via oral gavage. The volume of injection for intravenous (i.v.) and oral (p.o.) administration is 4 mL/kg and 8 mL/kg, respectively[1]. |
References: [1]. Yang H, et al. Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia. J Med Chem. 2018 May 24;61(10):4348-4369. | |
ETC-206 is an inhibitor of MAPK-interacting serine/threonine kinase 1 (MKNK1) and MKNK2 (IC50s = 0.064 and 0.086 ?M, respectively).1 It is selective for MKNK1 and MKNK2 over a panel of 104 kinases at 1 ?M. ETC-206 inhibits phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) in HeLa cells (IC50 = 0.321 ?M). In vivo, ETC-206 enhances tumor growth inhibition induced by dasatinib in a K562 mouse xenograft model. It also prevents weight gain in a mouse model of high-fat diet-induced obesity when administered at a dose of 100 mg/kg.2
1.Yang, H., Chennamaneni, L.R., Ho, M.W.T., et al.Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemiaJ. Med. Chem.61(10)4348-4369(2018) 2.Sandeman, L.Y., Kang, W.X., Wang, X., et al.Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesityMol. Metab.42101054(2020)
| Cas No. | 1464151-33-4 | SDF | |
| 别名 | 4-[6-[4-(4-吗啉基羰基)苯基]咪唑并[1,2-A]吡啶-3-基]苄腈 | ||
| Canonical SMILES | N#CC1=CC=C(C2=CN=C3C=CC(C4=CC=C(C(N5CCOCC5)=O)C=C4)=CN32)C=C1 | ||
| 分子式 | C25H20N4O2 | 分子量 | 408.45 |
| 溶解度 | DMSO : ≥ 50 mg/mL (122.41 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 | 2.4483 mL | 12.2414 mL | 24.4828 mL |
| 5 mM | 0.4897 mL | 2.4483 mL | 4.8966 mL |
| 10 mM | 0.2448 mL | 1.2241 mL | 2.4483 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。
First-in-Human, Healthy Volunteers Integrated Protocol of ETC-206, an Oral Mnk 1/2 Kinase Inhibitor Oncology Drug
Clin Transl Sci 2020 Jan;13(1):57-66.PMID:31343094DOI:10.1111/cts.12678.
In the last decade, drug development has tackled substantial challenges to improve efficiency and facilitate access to innovative medicines. Integrated clinical protocols and the investigation of targeted oncology drugs in healthy volunteers (HVs) have emerged as modalities with an increase in scope and complexity of early clinical studies and first-in-human (FIH) studies in particular. However, limited work has been done to explore the impact of these two modalities, alone or in combination, on the scientific value and on the implementation of such articulated studies. We conducted an FIH study in HVs with an oncology targeted drug, an Mnk 1/2 small molecule inhibitor. In this article, we describe results, advantages, and limitations of an integrated clinical protocol with an oncology drug. We further discuss and indicate points to consider when designing and conducting similar scientifically and operationally demanding FIH studies.
Progress in developing MNK inhibitors
Eur J Med Chem 2021 Jul 5;219:113420.PMID:33892273DOI:10.1016/j.ejmech.2021.113420.
The MNKs (mitogen-activated protein kinase-interacting protein kinases) phosphorylate eIF4E (eukaryotic initiation factor 4 E) at serine 209; eIF4E plays an important role in the translation of cytoplasmic mRNAs, all of which possess a 5' 'cap' structure to which eIF4E binds. Elevated levels of eIF4E, p-eIF4E and/or the MNK protein kinases have been found in many types of cancer, including solid tumors and leukemia. MNKs also play a role in metabolic disease. Regulation of the activities of MNKs (MNK1 and MNK2), control the phosphorylation of eIF4E, which in turn has a close relationship with the processes of tumor development, cell migration and invasion, and energy metabolism. MNK knock-out mice display no adverse effects on normal cells or phenotypes suggesting that MNK may be a potentially safe targets for the treatment of various cancers. Several MNK inhibitors or 'degraders' have been identified. Initially, some of the inhibitors were developed from natural products or based on other protein kinase inhibitors which inhibit multiple kinases. Subsequently, more potent and selective inhibitors for MNK1/2 have been designed and synthesized. Currently, three inhibitors (BAY1143269, eFT508 and ETC-206) are in various stages of clinical trials for the treatment of solid cancers or leukemia, either alone or combined with inhibitors of other protein kinase. In this review, we summarize the diverse MNK inhibitors that have been reported in patents and other literature, including those with activities in vitro and/or in vivo.
Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity
Mol Metab 2020 Dec;42:101054.PMID:32712434DOI:10.1016/j.molmet.2020.101054.
Objectives: Diet-driven obesity is increasingly widespread. Its consequences pose major challenges to human health and health care systems. There are MAP kinase-interacting kinases (MNKs) in mice, MNK1 and MNK2. Studies have demonstrated that mice lacking either MNK1 or MNK2 were partially protected against high-fat diet (HFD)-induced weight gain and insulin resistance. The aims of this study were to evaluate the phenotype of mice lacking both MNKs when given an HFD, to assess whether pharmacological inhibition of MNK function also protects against diet-induced obesity (DIO) and its consequences and to probe the mechanisms underlying such protection. Methods: Male wild-type (WT) C57Bl6 mice or mice lacking both MNK1 and MNK2 (double knockout, DKO) were fed an HFD or control diet (CD) for up to 16 weeks. In a separate study, WT mice were also given an HFD for 6 weeks, after which half were treated with the recently-developed MNK inhibitor ETC-206 daily for 10 more weeks while continuing an HFD. Metabolites and other parameters were measured, and the expression of selected mRNAs and proteins was assessed. Results: MNK-DKO mice were almost completely protected from HFD-induced obesity. Higher energy expenditure (EE) in MNK-DKO mice was observed, which probably reflects the changes in a number of genes or proteins linked to lipolysis, mitochondrial function/biogenesis, oxidative metabolism, and/or ATP consumption. The MNK inhibitor ETC-206 also prevented HFD-induced weight gain, confirming that the activity of the MNKs facilitates weight gain due to excessive caloric consumption. Conclusions: Disabling MNKs in mice, either genetically or pharmacologically, strongly prevents weight gain on a calorie-rich diet. This finding likely results from increased energy utilisation, involving greater ATP consumption, mitochondrial oxidative metabolism, and other processes.
Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia
J Med Chem 2018 May 24;61(10):4348-4369.PMID:29683667DOI:10.1021/acs.jmedchem.7b01714.
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.