Cobimetinib
(Synonyms: 考比替尼; GDC-0973; XL518) 目录号 : GC10033
A potent, orally available MEK1 inhibitor
Cas No.:934660-93-2
Sample solution is provided at 25 µL, 10mM.
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Cobimetinib is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) with IC50 value of 0.9 nM [1].
MEK is a kinase enzyme which selectively phosphorylates Ser/Thr and Tyr residues and involved in the mitogen-activated protein kinase (MAPK) signaling pathways that play an important role in regulation of cell proliferation, survival, differentiation, motility and angiogenesis [2].
In a KRAS G13D and B-RAF G464V mutant MDA-MB-231T breast adenocarcinoma cells, Cobimetinib inhibited MEK with IC50 value of 0.2 nM [1]. In pharmacokinetic-pharmacodynamic (PK-PD) model, Cobimetinib showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma [3].
In WM-266-4 xenograft mice, Cobimetinib decreased %pERK in tumor with IC50 values of 0.78 (WM-266-4) and 0.52 mM. Also, Cobimetinib (3.89 mM) increased IC50 value in WM-266-4 mice. In A375 xenograft mice, Cobimetinib (0.3-30 mg/kg) showed antitumor efficacy in a dose-dependent way. Cobimetinib is currently in phase I clinical trials as a potential antitumor agent [3].
References:
[1]. Rice KD, Aay N, Anand NK, et al. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett, 2012, 3(5): 416-421.
[2]. Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol, 2013, 6: 27.
[3]. Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res, 2012, 18(11): 3090-3099.
| Cell experiment [1]: | |
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Cell lines |
KRAS G13D and B-RAF G464V mutant MDA-MB-231T breast adenocarcinoma cell lines |
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Preparation method |
The solubility of this compound in DMSO is >26.6 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0-10 nM |
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Applications |
In the biochemical activity c-Raf/MEK1/ERK study, cobimetinib inhibited MEK1 activity with a IC50 value of 0.9 nM. Additionally, in MDA-MB-231T breast adenocarcinoma cells with KRAS G13D and B-RAF G464V mutant, cobimetinib was found to be able to inhibit MEK with the IC50 value of 0.2 nM. |
| Animal experiment [1]: | |
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Animal models |
MDA-MB-231T mouse xenograft model |
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Dosage form |
0.3-30 mg/kg, oral, qd |
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Application |
In an MDA-MB-231T efficacy study, cobimetinib demonstrated tumor growth inhibition values of 60 and 93% at 1 and 3 mg/kg, respectively, and statistically significant tumor regression was observed at higher doses. Overall, predicted ED50 and ED90 values were 0.6 and around 3 mg/kg/day, respectively, in the latter case corresponding to peak circulating plasma levels in the range of 130 nM. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1] Rice KD, Aay N, Anand NK, et al. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett, 2012, 3(5): 416-421. |
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| Cas No. | 934660-93-2 | SDF | |
| 别名 | 考比替尼; GDC-0973; XL518 | ||
| 化学名 | [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone | ||
| Canonical SMILES | C1CCNC(C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O | ||
| 分子式 | C21H21F3IN3O2 | 分子量 | 531.31 |
| 溶解度 | ≥ 26.55 mg/mL in DMSO, ≥ 33.53 mg/mL in EtOH with gentle warming | 储存条件 | Store at RT |
| 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 | 1.8821 mL | 9.4107 mL | 18.8214 mL |
| 5 mM | 0.3764 mL | 1.8821 mL | 3.7643 mL |
| 10 mM | 0.1882 mL | 0.9411 mL | 1.8821 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。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet