Background
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].
参考文献:
[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].
Protocol
| Cell experiment [1]: |
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Cell lines
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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
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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
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2-10 μM for 72 hours
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Applications
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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)
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| Animal experiment [2]: |
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Animal models
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BALB/c nude male mice
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Preparation Method
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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
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10, 30, or 100 mg/kg/d, five days on/two days off , oral
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Applications
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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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参考文献:
[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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