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Cobimetinib R-enantiomer

Alias: XL518 R-enantiomer, GDC-0973, RG7420 racemate;XL518; XL 518; XL-518 racemate; GDC0973 racemate; GDC 0973; GDC-0973; RG-7420; RG 7420racemate
Cat No.:V4525 Purity: ≥98%
Cobimetinib R-enantiomer is the less active R-enantiomer of Cobimetinib (formerly GDC-0973, RG7420 or XL-518;Cotellic) which is a small-molecule MEK1 inhibitor approved for cancer treatment.
Cobimetinib R-enantiomer
Cobimetinib R-enantiomer Chemical Structure CAS No.: 934660-94-3
Product category: New7
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
5mg
10mg
Other Sizes

Other Forms of Cobimetinib R-enantiomer:

  • Cobimetinib (GDC-0973, RG-7420, XL-518)
  • Cobimetinib hemifumarate
  • Cobimetinib racemate
Official Supplier of:
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Top Publications Citing lnvivochem Products
Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Cobimetinib R-enantiomer is the less active R-enantiomer of Cobimetinib (formerly GDC-0973, RG7420 or XL-518; Cotellic) which is a small-molecule MEK1 inhibitor approved for cancer treatment.

Biological Activity I Assay Protocols (From Reference)
ln 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.

ln Vivo
In 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 Protocol
1, 3, or 10 mg/kg
5 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.
References
:Cancer 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.
Physicochemical Properties
Molecular Formula
C21H21F3IN3O2
Molecular Weight
531.31
Exact Mass
531.063
CAS #
934660-94-3
Related CAS #
Cobimetinib;934660-93-2;Cobimetinib hemifumarate;1369665-02-0;Cobimetinib racemate;934662-91-6
PubChem CID
16222097
Appearance
White to off-white solid powder
LogP
4.12
Hydrogen Bond Donor Count
3
Hydrogen Bond Acceptor Count
7
Rotatable Bond Count
4
Heavy Atom Count
30
Complexity
624
Defined Atom Stereocenter Count
1
SMILES
C1CCN[C@H](C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O
InChi Key
BSMCAPRUBJMWDF-QGZVFWFLSA-N
InChi Code
InChI=1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m1/s1
Chemical Name
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2R)-piperidin-2-yl]azetidin-1-yl]methanone
Synonyms
XL518 R-enantiomer, GDC-0973, RG7420 racemate;XL518; XL 518; XL-518 racemate; GDC0973 racemate; GDC 0973; GDC-0973; RG-7420; RG 7420racemate
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 100 mg/mL (188.2 mM)
Water:<1 mg/mL
Ethanol: 47 mg/mL (88.46 mM)
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.75 mg/mL (5.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.75 mg/mL (5.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.75 mg/mL (5.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.


Solubility in Formulation 4: 5% DMSO+30% PEG 300+5% Tween 80+ddH2O:5mg/mL

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.8821 mL 9.4107 mL 18.8214 mL
5 mM 0.3764 mL 1.8821 mL 3.7643 mL
10 mM 0.1882 mL 0.9411 mL 1.8821 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

  • Calculate the Mass of a compound required to prepare a solution of known volume and concentration
  • Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
  • Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume
An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?
  • Enter 350.26 in the Molecular Weight (MW) box
  • Enter 10 in the Concentration box and choose the correct unit (mM)
  • Enter 5 in the Volume box and choose the correct unit (mL)
  • Click the “Calculate” button
  • The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
  • Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
  • Enter 25 into the Concentration (End) box and select the correct unit (mM)
  • Enter 25 into the Volume (End) box and choose the correct unit (mL)
  • Click the “Calculate” button
  • The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box
g/mol

Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:
  • To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.
Definitions of molecular mass, molecular weight, molar mass and molar weight:
  • Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
  • Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.
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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

  • Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
  • Click the “Calculate” button
  • The answer appears in the Volume (to add to vial) box
In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
             (2) Be sure to add the solvent(s) in order.

Biological Data
  • Cobimetinib R-enantiomer
    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 R-enantiomer


    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 R-enantiomer


    GDC-0973 single-agent efficacy and pharmacodynamic (PD) studies in BRAFV600Eand 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 R-enantiomer


    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 R-enantiomer


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

  • Cobimetinib R-enantiomer


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

    Cobimetinib R-enantiomer

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

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