Cobimetinib

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Chemical Structure| 934660-93-2 同义名 : 可美替尼 ;XL518; GDC-0973; RG-7420
CAS号 : 934660-93-2
货号 : A181766
分子式 : C21H21F3IN3O2
纯度 : 99%+
分子量 : 531.31
MDL号 : MFCD22124461
存储条件：

Pure form Keep in dark place, inert atmosphere, 2-8°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(94.11 mM)，配合低频超声，并水浴加热至45℃助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
生物活性
靶点

  • MEK1

    MEK1, IC50:4.2 nM
描述 The Ras-Raf-MEK pathway is overactive in many human cancers, such as melanoma and NSCLC. Cobimetinib, also called as GDC-0973 or RG7420, is a potent and highly selective inhibitor of MEK1 with IC50 value of 4.2 nM (measured by a kinase biochemical assays). Cobimetinib shows strong cellular potency particularly in BRAF or KRAS mutant cancer cell lines (in a detail, 80% of BRAF mutant lines were sensitive to Cobimetinib, 54% of lines carrying oncogenic mutations in KRAS or NRAS were sensitive and 35% of the remaining lines in test were sensitive). Consistent with this, BRAFV600E mutant melanoma tumor models showed higher sensitivity to BRAFV600E mutant melanoma tumor models at dose of 1 - 10 mg/kg, PO, QD x 3. Cobimetinib showed good pharmacodynamics, as treatment of 10 mg/kg dose of Cobimetinib cansuppress p-ERK 75% at 2 - 24 hours in the A375.X1 model[1]. Cobimetinib combined with vemurafenib was approved by FDA for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation[2].
作用机制 Cobimetinib is an ATP-noncompetitive allosteric inhibitor[3].
细胞研究
细胞系 浓度 检测类型 检测时间 活性说明 数据源
human COLO205 cells Function assay Inhibition of B-raf V600E mutant in human COLO205 cells assessed as reduction of ERK1/ERK2 phosphorylation, IC50=1.8 nM 22315332
human COLO205 cells Proliferation assay Antiproliferative activity against human COLO205 cells expressing B-raf V600E mutant, IC50=8 nM 22315332
human MDA-MB-231T cells Function assay 1 h Inhibition of MEK-mediated ERK T202/Y204 phosphorylation in human MDA-MB-231T cells after 1 hr by immunoblotting， IC50=0.2 nM 24900486
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.88mL

0.38mL

0.19mL

9.41mL

1.88mL

0.94mL

18.82mL

3.76mL

1.88mL
参考文献

[1]Hoeflich KP, Merchant M, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012 Jan 1;72(1):210-9.

[2]Cobimetinib: A Novel MEK Inhibitor for Metastatic Melanoma

[3]Rice KD, Aay N, et al. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett. 2012 Apr 9;3(5):416-21.

[4]Kawaguchi K, Igarashi K, et al. MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX). Oncotarget. 2017 Jul 18;8(29):47490-47496.

[5]Choo EF, Belvin M, et al. Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions. Drug Metab Dispos. 2012 May;40(5):919-27.