EMD-1214063
(Synonyms: 特泊替尼) 目录号 : GC10466
EMD-1214063 (Tepotinib, MSC2156119J) is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor .
Cas No.:1100598-32-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Triple-negative breast cancer cell lines (MDA-MB-468, HCC-1395, and MDA-MB-231) and hormone receptor positive cell line (T47D) |
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Preparation Method |
Cells were seeded in 96-well microplates in medium supplemented with 5% FBS and penicillin/streptavidin. The optimal cell number for each cell line was determined to ensure that each was in growth phase at the end of the assay (~70% confluency). Cells were allowed to attach for 24 hours. The media was changed to low FBS (2%) and drugs with different combinations were added (cetuximab 200ug/mL, gefitinib 0.25-8 umol/L and EMD-1214063 2-10 μM). Cells were incubated at 37°C for 72 hours. |
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Reaction Conditions |
2-10 µM for 72 hours |
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Applications |
These cell lines were essentially resistant to both gefitinib and EMD-1214063 as single agents. The inhibitory effect of combined treatment with gefitinib and EMD-1214063 was significantly enhanced compared with single agent therapy in MDA-MB-468 cells but not in the other cell lines (MDA-MB-231, HCC1395, and T47D) |
| Animal experiment [2]: | |
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Animal models |
BALB/c nude male mice |
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Preparation Method |
The patient-derived hepatocellular carcinoma (HCC) cells were subcutaneously inoculated in male BALB/c nude mice. When the tumors reached approximately 1 cm in diameter, subcutaneous tumors were collected and cut into pieces of about 2–3 mm3 and inoculated into the left lobe of the liver of male BALB/c nude mice.Mice were treated orally five days on/two days off with either vehicle combination (n = 10; 20% Solutol/80% 100 mM Na-acetate buffer, pH 5.5 ), EMD-1214063 (n = 10; 10, 30, or 100 mg/kg), sorafenib (n = 10; 50 mg/kg), or rapamycin (n = 10; 3 mg/kg) as single-agent treatment. In addition, EMD-1214063 (10 mg/kg) was given as a combination treatment with sorafenib (n = 10, 50 mg/kg) or rapamycin (n = 10; 3 mg/kg). Treatment was started seven days after orthotopic implantation of tumor fragments and terminated after five weeks. |
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Dosage form |
10, 30, or 100 mg/kg/d, five days on/two days off , oral |
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Applications |
The intrahepatic tumor size and weight were significantly lower in EMD-1214063 treated mice compared to the control group. EMD-1214063 treatment reduced the number of metastatic foci in the lungs of mice bearing orthotopic MHCC97H tumors, compared to the control group. |
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References: [1] : Sohn J, Liu S, Parinyanitikul N, et al. cMET activation and EGFR-directed therapy resistance in triple-negative breast cancer[J]. Journal of Cancer, 2014, 5(9): 745. [2] :Bladt F, Friese-Hamim M, Ihling C, et al. The c-Met inhibitor MSC2156119J effectively inhibits tumor growth in liver cancer models[J]. Cancers, 2014, 6(3): 1736-1752. |
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EMD-1214063 (Tepotinib, MSC2156119J) is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor [1]. EMD-1214063 inhibited recombinant human c-Met kinase with an average IC50 of 3 nmol/L [2].
EMD-1214063 treated A549 cells resulted in inhibition of HGF-induced c-Met phosphorylation, with an average IC50 of 6 nmol/L [2]. The inhibitory effect of combined treatment with gefitinib (0.25-8 μM) and EMD-1214063 (2-10 μM) was significantly enhanced compared with single agent therapy in MDA-MB-468 cells [3].
EMD-1214063(5, 15 mg/kg) treated EBC-1 non-small cell lung cancer tumor cells bearing mice resulted in effective inhibition or complete tumor regression [1]. EMD-1214063 induced dose-dependent tumor growth inhibition in mice bearing human pancreatic carcinoma KP-4 tumors . Daily administration of EMD 1214063 at 200 mg/kg resulted in partial tumor regressions in 60% of tumor bearing mice [1].The combination of EMD-1214063 (100 mg/kg) with rociletinib (100 mg/kg) caused complete tumor regression over the treatment period of 21 d , with no regrowth during the observation period following withdrawal of treatment, in the model of EGFR TKI-resistant tumors with high HGF/c-Met expression [4].EMD-1214063 (100 mg/kg) in combination with afatinib (5 mg/kg) caused complete tumor regression with no regrowth during the period of observation in PC-9 xenografts [4].
References:
[1]. Naing A, Falchook G S, Fu S, et al. A Phase I Dose-Escalation Study of emd 1214063, an Oral Selective CMET Inhibitor, in Patients with Advanced Solid Tumors[J]. Annals of Oncology, 2012, 23: xi21.
[2]. Bladt F, Faden B, Friese-Hamim M, et al. EMD 1214063 and EMD 1204831 Constitute a New Class of Potent and Highly Selective c-Met InhibitorsEMD 1214063 and EMD 1204831, a New Class of c-Met Inhibitors[J]. Clinical Cancer Research, 2013, 19(11): 2941-2951.
[3]. Sohn J, Liu S, Parinyanitikul N, et al. cMET activation and EGFR-directed therapy resistance in triple-negative breast cancer[J]. Journal of Cancer, 2014, 5(9): 745.
[4]. Friese-Hamim M, Bladt F, Locatelli G, et al. The selective c-Met inhibitor tepotinib can overcome epidermal growth factor receptor inhibitor resistance mediated by aberrant c-Met activation in NSCLC models[J]. American journal of cancer research, 2017, 7(4): 962.
EMD-1214063（Tepotinib，MSC2156119J）是一种新型强效、高选择性、可逆、ATP 竞争性小分子 c-Met 抑制剂[1]。 EMD-1214063 抑制重组人 c-Met 激酶，平均 IC50 为 3 nmol/L [2]。
EMD-1214063 处理 A549 细胞可抑制 HGF 诱导的 c-Met 磷酸化，平均 IC50 为 6 nmol/L [2]。与单药治疗相比，吉非替尼 (0.25-8 μM) 和 EMD-1214063 (2-10 μM) 联合治疗对 MDA-MB-468 细胞的抑制作用显着增强[3]。
EMD-1214063(5, 15 mg/kg) 处理荷 EBC-1 非小细胞肺癌肿瘤细胞的小鼠，导致有效抑制或肿瘤完全消退[1]。 EMD-1214063 在携带人胰腺癌 KP-4 肿瘤的小鼠中诱导剂量依赖性肿瘤生长抑制。每日给予 200 mg/kg 的 EMD 1214063 导致 60% 的荷瘤小鼠肿瘤部分消退[1]。EMD-1214063 (100 mg/kg) 与 rociletinib (100 mg /kg) 在具有高 HGF/c-Met 表达的 EGFR TKI 耐药肿瘤模型中，在 21 天的治疗期间导致肿瘤完全消退，在停止治疗后的观察期内没有再生长 [4] .EMD-1214063 (100 mg/kg) 联合阿法替尼 (5 mg/kg) 在 PC-9 异种移植物的观察期间导致肿瘤完全消退，没有再生长 [4].
| Cas No. | 1100598-32-0 | SDF | |
| 别名 | 特泊替尼 | ||
| 化学名 | 3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile | ||
| Canonical SMILES | CN1CCC(CC1)COC2=CN=C(N=C2)C3=CC(=CC=C3)CN4C(=O)C=CC(=N4)C5=CC=CC(=C5)C#N | ||
| 分子式 | C29H28N6O2 | 分子量 | 492.57 |
| 溶解度 | ≥ 4.93 mg/mL in DMSO, <2.52 mg/mL in EtOH, <2.56 mg/mL in Water | 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 | 2.0302 mL | 10.1508 mL | 20.3017 mL |
| 5 mM | 0.406 mL | 2.0302 mL | 4.0603 mL |
| 10 mM | 0.203 mL | 1.0151 mL | 2.0302 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。
EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors
Purpose: The mesenchymal-epithelial transition factor (c-Met) receptor, also known as hepatocyte growth factor receptor (HGFR), controls morphogenesis, a process that is physiologically required for embryonic development and tissue repair. Aberrant c-Met activation is associated with a variety of human malignancies including cancers of the lung, kidney, stomach, liver, and brain. In this study, we investigated the properties of two novel compounds developed to selectively inhibit the c-Met receptor in antitumor therapeutic interventions. Experimental design: The pharmacologic properties, c-Met inhibitory activity, and antitumor effects of EMD 1214063 and EMD 1204831 were investigated in vitro and in vivo, using human cancer cell lines and mouse xenograft models. Results: EMD 1214063 and EMD 1204831 selectively suppressed the c-Met receptor tyrosine kinase activity. Their inhibitory activity was potent [inhibitory 50% concentration (IC50), 3 nmol/L and 9 nmol/L, respectively] and highly selective, when compared with their effect on a panel of 242 human kinases. Both EMD 1214063 and EMD 1204831 inhibited c-Met phosphorylation and downstream signaling in a dose-dependent fashion, but differed in the duration of their inhibitory activity. In murine xenograft models, both compounds induced regression of human tumors, regardless of whether c-Met activation was HGF dependent or independent. Both drugs were well tolerated and induced no substantial weight loss after more than 3 weeks of treatment. Conclusions: Our results indicate selective c-Met inhibition by EMD 1214063 and EMD 1204831 and strongly support clinical testing of these compounds in the context of molecularly targeted anticancer strategies.
Tepotinib
No information is available on the clinical use of tepotinib during breastfeeding. Because tepotinib is 98% bound to plasma proteins, the amount in milk is likely to be low. However, because of its potential toxicity in the breastfed infant and its half-life of 32 hours, the manufacturer recommends that breastfeeding be discontinued during tepotinib therapy and for 1 week after the last dose.
The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models
The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling.
Lassa Virus Cell Entry via Dystroglycan Involves an Unusual Pathway of Macropinocytosis
The pathogenic Old World arenavirus Lassa virus (LASV) causes a severe hemorrhagic fever with a high rate of mortality in humans. Several LASV receptors, including dystroglycan (DG), TAM receptor tyrosine kinases, and C-type lectins, have been identified, suggesting complex receptor use. Upon receptor binding, LASV enters the host cell via an unknown clathrin- and dynamin-independent pathway that delivers the virus to late endosomes, where fusion occurs. Here we investigated the mechanisms underlying LASV endocytosis in human cells in the context of productive arenavirus infection, using recombinant lymphocytic choriomeningitis virus (rLCMV) expressing the LASV glycoprotein (rLCMV-LASVGP). We found that rLCMV-LASVGP entered human epithelial cells via DG using a macropinocytosis-related pathway independently of alternative receptors. Dystroglycan-mediated entry of rLCMV-LASVGP required sodium hydrogen exchangers, actin, and the GTPase Cdc42 and its downstream targets, p21-activating kinase-1 (PAK1) and Wiskott-Aldrich syndrome protein (N-Wasp). Unlike other viruses that enter cells via macropinocytosis, rLCMV-LASVGP entry did not induce overt changes in cellular morphology and hardly affected actin dynamics or fluid uptake. Screening of kinase inhibitors identified protein kinase C, phosphoinositide 3-kinase, and the receptor tyrosine kinase human hepatocyte growth factor receptor (HGFR) to be regulators of rLCMV-LASVGP entry. The HGFR inhibitor EMD 1214063, a candidate anticancer drug, showed antiviral activity against rLCMV-LASVGP at the level of entry. When combined with ribavirin, which is currently used to treat human arenavirus infection, EMD 1214063 showed additive antiviral effects. In sum, our study reveals that DG can link LASV to an unusual pathway of macropinocytosis that causes only minimal perturbation of the host cell and identifies cellular kinases to be possible novel targets for therapeutic intervention.
Importance: Lassa virus (LASV) causes several hundred thousand infections per year in Western Africa, with the mortality rate among hospitalized patients being high. The current lack of a vaccine and the limited therapeutic options at hand make the development of new drugs against LASV a high priority. In the present study, we uncover that LASV entry into human cells via its major receptor, dystroglycan, involves an unusual pathway of macropinocytosis and define a set of cellular factors implicated in the regulation of LASV entry. A screen of kinase inhibitors revealed HGFR to be a possible candidate target for antiviral drugs against LASV. An HGFR candidate inhibitor currently being evaluated for cancer treatment showed potent antiviral activity and additive drug effects with ribavirin, which is used in the clinic to treat human LASV infection. In sum, our study reveals novel fundamental aspects of the LASV-host cell interaction and highlights a possible candidate drug target for therapeutic intervention.
Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation
Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2-M cell-cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1-S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1-S and G2-M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wild-type p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell-cycle distribution profiling indicates constantly lower G1 and higher G2-M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared with the parental counterpart.
Implications: The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, as p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA-damaging agents for MET-positive/p53-negative tumors.