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Description: Cobimetinib (formerly GDC0973, RG7420, XL518) is an orally bioavailable and selective small-molecule inhibitor of MEK1 with potential anticancer activity. It inhibits MEK1 with an IC50 of 4.2 nM. GDC-0973 acts by specifically binding to and inhibiting the catalytic activity of MEK1, leading to hte inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation.
References: Cancer Res. 2012 Jan 1;72(1):210-9; JEJNMMI Res. 2012 May 31;2(1):22.
Related CAS: 1369665-02-0 (fumarate); 934660-94-3 (R-enantiomer); 934662-91-6 (racemate); 934660-93-2 (free base)
GDC-0973, RG 7420; XL 518; XL 518; XL-518; GDC0973; GDC0973; RG-7420; RG7420
Chemical Name: (S)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-(piperidin-2-yl)cyclobutyl)methanone.
InChi Key: FIAWSLMDMMCNMU-HHCSFTFJSA-N
InChi Code: InChI=1S/C22H22F3IN2O2/c23-15-6-5-14(20(19(15)25)28-17-7-4-13(26)9-16(17)24)21(29)12-10-22(30,11-12)18-3-1-2-8-27-18/h4-7,9,12,18,27-28,30H,1-3,8,10-11H2/t12?,18-,22?/m0/s1
SMILES Code: O=C(C1=CC=C(F)C(F)=C1NC2=CC=C(I)C=C2F)C3CC([[email protected]]4NCCCC4)(O)C3
Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2
In vitro activity: Cobimetinib shows strong activity on cell growth inhibtion in a broad panel of tumor types, particularly in BRAF or KRAS mutant cancer cell lines. In combination with GDC-0941, GDC-0973 results in reduced viability, pathway inhibition, and increased apoptosis in 888MEL and A2058 cells. Coadministration of GDC-0973 and vemurafenib significantly increases decreased levels of GLUT-1 on the cellular membrane across all BRAFV600E lines.
Kinase Assay: Cobimetinib (GDC-0973, RG7420) is a potent, selective and oral MEK1 inhibitor with an IC50 of 4.2 nM for MEK1.
Cell Assay: The EC50 values of Cobimetinib (GDC-0973) for 888MEL and A2058 cells are 0.2 μM, 10 μM, respectivelly. Melanoma cells are treated with EC50concentration of MEK and PI3K inhibitors for 24 hours (888MEL: 0.05 μM GDC-0973, 2.5 μM GDC-0941; A2058: 2.5 μM GDC-0973, 2.5 μM GDC-0941). Mitochondrial OXPHOS limits cell death induced by cobimetinib (100 nM) in melanoma with constitutive MAPK activation in A375 cells.
Purity ≥98%
COA
MSDS
NMR
FDG-PET imaging. FDG-PET imaging is effective for monitoring vemurafenib and GDC-0973 combination drug action in BRAFV600E mutant and resistant xenografts. EJNMMI Res. 2012; 2: 22.
GDC-0973 is a selective, potent MEK inhibitor with efficacy in BRAF and RAS mutant cell lines. A, chemical structure of GDC-0973. B, GDC-0973 was tested in a panel of cell lines in 96-hour viability assays. Cancer Res. 2012 Jan 1;72(1):210-9.
GDC-0973 single-agent efficacy and pharmacodynamic (PD) studies in BRAFV600E and KRAS mutant tumor models. Dose-ranging efficacy studies were carried out in the (A) A375.X1 and (B) NCI-H2122 tumor xenograft models. Cancer Res. 2012 Jan 1;72(1):210-9.
Combination of GDC-0973 + GDC-0941 results in reduced viability, pathway inhibition, and increased apoptosis. A, the 888MEL and A2058 BRAF mutant melanoma cell lines were treated with increasing concentrations of GDC-0973 and GDC-0941 as single agents and in combination and assayed in a 96-hour viability assay.Cancer Res. 2012 Jan 1;72(1):210-9.
GDC-0973 and GDC-0941 combination results in TGI when dosed daily. Cancer Res. 2012 Jan 1;72(1):210-9.
GDC-0973 and GDC-0941 combination results in TGI when dosed intermittently.
Transient treatment of GDC-0973 + GDC-0941 results in apoptosis and prolonged accumulation of Bim.