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Purity: ≥98%
Cobimetinib hemifumarate (formerly also known as RG7420; XL518; GDC0973), the hemifumarate salt of cobimetinib, is an oral, highly potent and selective MEK1 inhibitor with potential antineoplastic activity. IWith an IC50 of 4.2 nM, it blocks MEK1.
| Targets |
MEK1 (IC50 = 4.2 nM)
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| ln Vitro |
Cobimetinib (GDC-0973) has an EC50 of 0.2 μM and 10 μM for 888MEL and A2058 cells, respectively. (888MEL: 0.05 μM GDC-0973, 2.5 μM GDC-0941; A2058: 2.5 μM GDC-0973, 2.5 μM GDC-0941)[1] Melanoma cells are treated with EC50 concentrations of MEK and PI3K inhibitors for 24 hours. When cobimetinib (100 nM) is used to treat melanoma cells in A375 cells, mitochondrial OXPHOS limits the amount of cell death that is induced[4].
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| ln Vivo |
Treatment with Cobimetinib (GDC-0973) up to 5 mg/kg causes moderate TGI in the NCI-H2122 KRASG12C mutant non-small cell lung carcinoma (NSCLC) xenograft model, and at 10 mg/kg approaches tumor stasis[1]. GDC-0973 and GDC-0941 are given to mice with the A2058 tumor daily (QD) or every third day (Q3D), either separately or together. For GDC-0973 and GDC-0941, the population rate constants linked to tumor growth inhibition are 0.00102 and 0000651 μM-1 h-1, respectively[2]. Based on tumor concentrations in xenografted mice, the estimated in vivo IC50 values of %pERK decrease are 0.78 (WM-266-4) and 0.52 μM (A375) after single doses of GDC-0973 (1, 3, or 10 mg/kg, p.o.)[3].
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| Enzyme Assay |
Cobimetinib (GDC-0973, RG7420) is a potent, selective and oral MEK1 inhibitor with an IC50 of 4.2 nM for MEK1.
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| Animal Protocol |
Female NCR nude mice have had 5 million WM-266-4 melanoma cells intradermally implanted into the hind flank. The cells were resuspended in Hank balanced salt solution. Xenograft mice with tumor volumes of roughly 100 to 120 mm3 are randomly assigned to 4 single dose groups and 4 multiple dose groups on days 11 or 13 following the implantation. Mice in the single dose groups receive a single oral dose of the drug Cobimetinib (GDC-0973, expressed as free base equivalents), vehicle (water for injection USP), 1, 3, or 10 mg/kg one day after randomization and group assignment. For 14 days, mice in the multiple dose groups receive daily oral doses of the GDC-0973 1, 3, or 10 mg/kg, vehicle (water for injection USP), or both. On day 1 (single dose groups) or day 14 (multiple dose groups), plasma and tumor samples (n=3 per time point) are taken from euthanized mice predose and at 2, 4, 8, 16, 24, 72, and 168 hours postdose. Samples are kept until analysis at 80°C. Liquid chromatography/tandem mass spectrometry (LC/MS-MS) is used to assess the concentrations of GDC-0973 in tumor lysates and plasma. The assay's dynamic range is 0.004 to 35 μM.
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| References |
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| Additional Infomation |
Cobimetinib fumarate is a fumarate salt prepared from cobimetinib by reaction of one molecule of fumaric acid for every two molecules of cobimetinib. An inhibitor of mitogen-activated protein kinase that is used in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma. It has a role as an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor and an antineoplastic agent. It is a fumarate salt and an organoammonium salt. It contains a cobimetinib(1+).
See also: Cobimetinib (has active moiety). Drug Indication Cotellic is indicated for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. |
| Molecular Formula |
C₂₅H₂₅F₃IN₃O₆
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|---|---|---|
| Molecular Weight |
647.38
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| Exact Mass |
647.074
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| Elemental Analysis |
C, 46.87; H, 3.93; F, 9.67; I, 21.53; N, 7.13; O, 10.86
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| CAS # |
1369665-02-0
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| Related CAS # |
Cobimetinib;934660-93-2;Cobimetinib racemate;934662-91-6;Cobimetinib (R-enantiomer);934660-94-3
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| PubChem CID |
71491931
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| Appearance |
White to off-white solid powder
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| LogP |
3.832
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
18
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
68
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| Complexity |
743
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| Defined Atom Stereocenter Count |
2
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| SMILES |
IC1C=CC(=C(C=1)F)NC1=C(C(=CC=C1C(N1CC(C1)([C@@H]1CCCCN1)O)=O)F)F.IC1C=CC(=C(C=1)F)NC1=C(C(=CC=C1C(N1CC(C1)([C@@H]1CCCCN1)O)=O)F)F.OC(/C=C/C(=O)O)=O
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| InChi Key |
RESIMIUSNACMNW-BXRWSSRYSA-N
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| InChi Code |
InChI=1S/2C21H21F3IN3O2.C4H4O4/c2*22-14-6-5-13(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;5-3(6)1-2-4(7)8/h2*4-7,9,17,26-27,30H,1-3,8,10-11H2;1-2H,(H,5,6)(H,7,8)/b;;2-1+/t2*17-;/m00./s1
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| Chemical Name |
(E)-but-2-enedioic acid;[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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: ≥ 2.5 mg/mL (4.24 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 25.0 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: ≥ 2.5 mg/mL (4.24 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 25.0 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: ≥ 2.5 mg/mL (4.24 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: ≥ 2.5 mg/mL (4.24 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.5 mg/mL (4.24 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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 6: 5% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5447 mL | 7.7234 mL | 15.4469 mL | |
| 5 mM | 0.3089 mL | 1.5447 mL | 3.0894 mL | |
| 10 mM | 0.1545 mL | 0.7723 mL | 1.5447 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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