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].
Cobimetinib 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
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
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