| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
Cobimetinib R-enantiomer targets MEK1 and MEK2 (mitogen-activated protein kinase kinases 1 and 2), key components of the RAS/RAF/MEK/ERK signaling pathway. MEK1/2 are dual-specificity kinases that phosphorylate and activate ERK1/2, which regulate cell growth, survival, differentiation, and migration. The RAS/RAF/MEK/ERK pathway is frequently hyperactivated in cancer due to mutations in RAS or RAF, making MEK a key therapeutic target. Cobimetinib R-enantiomer is the less active R-enantiomer of cobimetinib compared to the S-enantiomer. It is used as a control compound in studies of enantiomer-selective MEK inhibition to distinguish specific effects of the active enantiomer from non-specific effects.
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| 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. Cobimetinib R-enantiomer demonstrates reduced in vitro activity against MEK1/2 compared to the active S-enantiomer. The compound is a selective MEK1/2 inhibitor. By inhibiting MEK1/2, cobimetinib blocks the activation of ERK1/2 and downstream signaling pathways that regulate cell growth and proliferation. The R-enantiomer is the less active form and is primarily used as a negative or low-activity control in studies of enantiomer-selective MEK inhibition. The compound's reduced potency makes it suitable for distinguishing enantiomer-specific effects of MEK inhibition from non-specific effects in cellular and biochemical assays. |
| 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
Cobimetinib R-enantiomer is used as a control compound in in vivo studies to distinguish the specific effects of MEK inhibition from non-specific effects. In tumor xenograft models, the R-enantiomer is administered alongside the active S-enantiomer to validate that the antitumor effects observed are specifically due to MEK inhibition. The compound's lack of significant antitumor efficacy compared to the active enantiomer confirms that the effects observed are specifically due to MEK inhibition. Cobimetinib (the active S-enantiomer) has been approved by the FDA for the treatment of advanced melanoma in combination with vemurafenib. The R-enantiomer is used as a research tool to study enantiomer selectivity and control for off-target effects. |
| Enzyme Assay |
The in vitro enzyme inhibition assay for Cobimetinib R-enantiomer measures the inhibition of MEK1 kinase activity. Recombinant human MEK1 enzyme is incubated with varying concentrations of Cobimetinib R-enantiomer (typically ranging from nanomolar to micromolar) in the presence of ATP and ERK2 as a substrate. The kinase reaction is allowed to proceed for a fixed period, and the extent of ERK2 phosphorylation is quantified. IC50 values are determined by fitting dose-response curves to the inhibition data and compared to the active S-enantiomer to confirm its lower potency. The compound is dissolved in DMSO and diluted in assay buffer to achieve the desired final concentrations. Appropriate positive controls (active MEK inhibitors) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
The in vitro cellular assay for Cobimetinib R-enantiomer is performed using cancer cell lines that are dependent on the MAPK/ERK pathway for proliferation, such as BRAF-mutant melanoma cell lines. Cells are cultured in appropriate medium and treated with varying concentrations of Cobimetinib R-enantiomer or vehicle control (DMSO) for specified time points. Cell viability and proliferation are assessed using assays such as MTT, CellTiter-Glo, or by direct cell counting. ERK1/2 phosphorylation status is assessed by Western blotting using phospho-specific antibodies. The effects of the R-enantiomer on cell viability and signaling are compared to those of the active S-enantiomer to confirm that the metabolic changes observed with the active compound are specifically due to MEK inhibition. The R-enantiomer serves as a critical control to rule out non-specific effects of the compound scaffold.
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| 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. In vivo animal experiments with Cobimetinib R-enantiomer are conducted in parallel with studies using the active S-enantiomer. Immunocompromised mice bearing human BRAF-mutant melanoma xenografts are randomized into treatment groups receiving the R-enantiomer, the active S-enantiomer, or vehicle control. The R-enantiomer is administered via oral gavage at doses comparable to those used for the active compound. Tumor volume is measured twice weekly, and body weight is monitored. At study endpoint, tumors are harvested for analysis of MEK target engagement, ERK phosphorylation, and markers of proliferation and apoptosis. The lack of significant antitumor efficacy with the R-enantiomer compared to the active enantiomer confirms that the effects observed are specifically due to MEK inhibition. |
| ADME/Pharmacokinetics |
Detailed pharmacokinetic (PK) parameters for Cobimetinib R-enantiomer are not extensively documented in publicly available sources. As the less active enantiomer of cobimetinib, the R-enantiomer is expected to have similar physicochemical properties to the active S-enantiomer, including a molecular weight of 531.31 and a chemical formula of C21H21F3IN3O2. The compound is soluble in DMSO for formulation purposes. For in vivo oral administration, the R-enantiomer is typically formulated using appropriate vehicles to ensure adequate solubility and stability. The compound should be stored under conditions recommended by the manufacturer to maintain stability and prevent degradation. Detailed PK parameters are available in the primary literature for cobimetinib and should be consulted for specific experimental planning.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for Cobimetinib R-enantiomer are not extensively documented in publicly available sources. As a research-grade compound, Cobimetinib R-enantiomer is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound should be stored according to the manufacturer's recommendations to maintain stability and prevent degradation. Toxicological data for cobimetinib (the active enantiomer) are available from preclinical and clinical studies and should be consulted for safety information.
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| References | |
| Additional Infomation |
Cobimetinib R-enantiomer is a research compound developed for studying enantiomer-selective MEK inhibition and for use as a control in studies of cobimetinib. The compound is the less active R-enantiomer of cobimetinib, an FDA-approved small-molecule MEK1/2 inhibitor indicated for BRAF V600-mutated metastatic melanoma in combination with vemurafenib. Cobimetinib R-enantiomer is also referred to as GDC-0973 R-enantiomer or XL-518 R-enantiomer. The R-enantiomer is used to distinguish enantiomer-specific effects of MEK inhibition from non-specific effects in biochemical and cellular assays. Cobimetinib R-enantiomer is not currently in clinical trials nor approved for therapeutic use; it remains an investigational tool compound for preclinical research. Cobimetinib R-enantiomer is available from various chemical suppliers for research purposes. Its utility lies in its ability to serve as a control for enantiomer-selective MEK inhibition studies.
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| Molecular Formula |
C21H21F3IN3O2
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| Molecular Weight |
531.31
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| Exact Mass |
531.063
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| CAS # |
934660-94-3
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| Related CAS # |
Cobimetinib;934660-93-2;Cobimetinib hemifumarate;1369665-02-0;Cobimetinib racemate;934662-91-6
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| PubChem CID |
16222097
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| Appearance |
White to off-white solid powder
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| LogP |
4.12
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
624
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| Defined Atom Stereocenter Count |
1
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| 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
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| InChi Key |
BSMCAPRUBJMWDF-QGZVFWFLSA-N
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| 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
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| Chemical Name |
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2R)-piperidin-2-yl]azetidin-1-yl]methanone
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| 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. View More
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. Solubility in Formulation 4: 5% DMSO+30% PEG 300+5% Tween 80+ddH2O:5mg/mL |
| 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.
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.
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 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 BRAFV600Eand 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. |
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 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. |
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