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Cobimetinib R-enantiomer 934660-94-3

Cobimetinib R-enantiomer 934660-94-3

CAS No.: 934660-94-3

Cobimetinib R-enantiomer is the less active R-enantiomer of Cobimetinib (formerly GDC-0973, RG7420 or XL-518; Cotellic)
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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.



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)

Biological Activity


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.

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.
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.

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Is for research use only, not for human use. We do not sell to patients.