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    Cobimetinib (GDC-0973, RG-7420, XL-518)
    Cobimetinib (GDC-0973, RG-7420, XL-518)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0453
    CAS #: 934660-93-2 (free base)Purity ≥98%

    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) 

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    Molecular Weight (MW)531.31
    FormulaC21H21F3IN3O2 
    CAS No.934660-93-2
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (188.2 mM)
    Water: <1 mg/mL
    Ethanol: 47 mg/mL (88.46 mM)
    Solubility (In vivo)5% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5 mg/mL
    Synonym

    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 


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    In Vitro

    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.

    In VivoIn mice bearing BRAFV600E and KRAS mutant tumors, Cobimetinib (10 mg/kg, p.o.) produces antitumor efficacy, and the combination of GDC-0973 and GDC-0941 show improved efficacy. In mice bearing drug-resistant A375 xenografts, combination of GDC-0973 and GDC-0941 induces decreased levels of hexokinase II, c-RAF, Ksr and p-MEK protein
    Animal model5 million WM-266-4 melanoma cells are resuspended in Hank balanced salt solution and implanted intradermally into the hind flank of female NCR nude mice. On days 11 or 13 after the implantation, xenograft mice with tumor volumes of approximately 100 to 120 mm3 are randomLy assigned to 8 groups (n=27 per group), 4 single dose groups and 4 multiple dose groups. One day after randomization and group assignment, mice in the single dose groups are given a single oral dose of vehicle (water for injection USP), 1, 3, or 10 mg/kg of Cobimetinib (GDC-0973, expressed as free base equivalents). Mice in the multiple dose groups are given daily oral doses of vehicle (water for injection USP), 1, 3, or 10 mg/kg of GDC-0973 for 14 days. Plasma and tumor samples (n=3 per time point) are collected from euthanized mice predose and at 2, 4, 8, 16, 24, 72, 120, and 168 hours postdose on day 1 (single dose groups) or day 14 (multiple dose groups). Samples are stored at −80°C until analysis. GDC-0973 concentrations in plasma and tumor lysates are determined using liquid chromatography/tandem mass spectrometry (LC/MS-MS). The dynamic range of the assay is 0.004 to 35 μM.
    Formulation & Dosage1, 3, or 10 mg/kg
    ReferencesCancer Res. 2012 Jan 1;72(1):210-9; JEJNMMI Res. 2012 May 31;2(1):22.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Cobimetinib (GDC-0973, RG7420)

    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.

    Cobimetinib (GDC-0973, RG7420)

    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.  2012 Jan 1;72(1):210-9.

    Cobimetinib (GDC-0973, RG7420)

    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.  2012 Jan 1;72(1):210-9.

    Cobimetinib (GDC-0973, RG7420)

    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. 2012 Jan 1;72(1):210-9.

    Cobimetinib (GDC-0973, RG7420)

    GDC-0973 and GDC-0941 combination results in TGI when dosed daily.   2012 Jan 1;72(1):210-9. 

    Cobimetinib (GDC-0973, RG7420)

    GDC-0973 and GDC-0941 combination results in TGI when dosed intermittently.


    Cobimetinib (GDC-0973, RG7420)

    Transient treatment of GDC-0973 + GDC-0941 results in apoptosis and prolonged accumulation of Bim.


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