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Cobimetinib

现货
Catalog No.
A3321
MEK选择性抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 2,100.00
现货
5mg
¥ 1,400.00
现货
10mg
¥ 2,100.00
现货
25mg
¥ 4,200.00
现货
50mg
¥ 6,300.00
现货

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Background

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.

文献引用

1. White SM, Avantaggiati ML, et al. "YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells." Dev Cell. 2019 May 6;49(3):425-443.e9. PMID:31063758
2. Kulshrestha A, Katara GK, et al. "Targeting V-ATPase Isoform Restores Cisplatin Activity in Resistant Ovarian Cancer: Inhibition of Autophagy, Endosome Function, and ERK/MEK Pathway." J Oncol. 2019 Apr 1;2019:2343876. PMID:31057611
3. Brunen D, de Vries RC, et al. "PIM Kinases Are a Potential Prognostic Biomarker and Therapeutic Target in Neuroblastoma." Mol Cancer Ther. 2018 Apr;17(4):849-857. PMID:29440296
4. Gutjahr JC, Szenes E, et al. "Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia." Blood. 2018 Mar 22;131(12):1337-1349. PMID:29352038

Chemical Properties

StorageStore at -20°C
M.Wt531.31
Cas No.934660-93-2
FormulaC21H21F3IN3O2
SynonymsGDC-0973;XL-518;GDC 0973;XL 518;GDC0973;XL518
Solubility≥26.55 mg/mL in DMSO, ≥33.53 mg/mL in EtOH with gentle warming, <2.22 mg/mL in H2O
Chemical Name[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone
SDFDownload SDF
Canonical SMILESC1CCNC(C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1]:

细胞系

同时携带KRAS G13D和B-RAF G464V突变的MDA-MB-231T乳腺癌细胞系

溶解方法

在DMSO中的溶解度> 26.6 mg/mL。为了获得更高浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

0-10 nM

应用

在生物化学活性c-Raf / MEK1 / ERK研究中,cobimetinib抑制MEK1活性,IC50值为0.9 nM。 另外,在具有KRAS G13D和B-RAF G464V突变体的MDA-MB-231T乳腺癌细胞中,研究发现cobimetinib能够抑制MEK,IC50值为0.2 nM。

动物实验 [1]:

动物模型

MDA-MB-231T小鼠异种移植模型

剂量

0.3-30 mg/kg,口服,一天一次

应用

在MDA-MB-231T疗效研究中,cobimetinib在1和3mg / kg下分别显示出60和93%的肿瘤生长抑制率,并且在较高剂量下观察到统计学显著的肿瘤消退。预测出的ED50和ED90值分别为0.6和约3mg / kg /天,后一种情况对应于130 nM范围内的峰值血浆水平。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

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.

质量控制

化学结构

Cobimetinib

相关生物数据

Cobimetinib

相关生物数据

Cobimetinib

相关生物数据

Cobimetinib