| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
Purity: ≥98%
| Targets |
Cobimetinib racemate targets MEK1 (mitogen-activated protein kinase kinase 1), a key component of the RAS/RAF/MEK/ERK signaling pathway. MEK1 is a dual-specificity kinase that phosphorylates and activates ERK1/2, which then regulate cell proliferation, 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 racemate is a potent, selective MEK1 inhibitor with an IC50 of 4.2 nM. It is also an Akt inhibitor. The racemate contains both enantiomers of Cobimetinib and is used as a research tool to study MEK inhibition.
|
|---|---|
| ln Vitro |
Cobimetinib shows strong activity on cell growth inhibtion in a broad panel of tumor types, particularly in BRAF or KRAS mutant cancer cell lines. GDC-0973 causes 888MEL and A2058 cells to undergo more apoptosis, pathway inhibition, and reduced viability when combined with GDC-0941. All BRAFV600E lines have increased levels of GLUT-1 on the cellular membrane following coadministration of GDC-0973 and vemurafenib.
Cobimetinib racemate demonstrates potent in vitro activity against MEK1 with an IC50 of 4.2 nM. The compound inhibits MEK1 and MEK2, key components of the MAPK/ERK signaling pathway. By inhibiting these kinases, Cobimetinib racemate blocks the activation of ERK1/2 and downstream signaling pathways that regulate cell growth and proliferation. The compound is also an Akt inhibitor. Cobimetinib racemate's potent MEK inhibition makes it a valuable tool for studying the role of the MAPK/ERK pathway in cancer and other diseases. The compound's activity has been characterized in various in vitro systems, confirming its mechanism of action as a MEK inhibitor. |
| ln Vivo |
Cobimetinib (10 mg/kg, p.o.) and GDC-0973 and GDC-0941 together exhibit improved antitumor efficacy in mice with BRAFV600E and KRAS mutant tumors. Combining GDC-0973 and GDC-0941 results in lower levels of hexokinase II, c-RAF, Ksr, and p-MEK protein in mice with drug-resistant A375 xenografts.
Cobimetinib racemate has been evaluated in vivo for its antitumor activity. Cobimetinib (the active enantiomer) was approved in 2015 as an anticancer drug for the treatment of melanoma, used alone or in combination with vemurafenib or with both vemurafenib and atezolizumab. The racemate is used in preclinical research to explore the therapeutic potential of MEK inhibition in oncology and to study pathway-specific cellular mechanisms. In preclinical models, Cobimetinib has demonstrated efficacy in suppressing tumor growth in BRAF-mutant melanoma and other cancers. The compound's oral bioavailability supports its utility for in vivo studies. |
| Enzyme Assay |
Cobimetinib (GDC-0973, RG7420) is a potent, selective and oral MEK1 inhibitor with an IC50 of 4.2 nM for MEK1.
The in vitro enzyme inhibition assay for Cobimetinib racemate measures the inhibition of MEK1 kinase activity. Recombinant human MEK1 enzyme is incubated with varying concentrations of Cobimetinib racemate (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 using techniques such as fluorescence polarization, luminescence-based kinase assays, or Western blotting with phospho-specific antibodies. The IC50 value of 4.2 nM is determined by fitting dose-response curves to the inhibition data. The compound is dissolved in DMSO and diluted in assay buffer to achieve the desired final concentrations. Selectivity is assessed by testing the compound against a panel of other kinases. Appropriate positive controls (known MEK inhibitors) and negative controls (DMSO vehicle) are included in each assay run. |
| Cell Assay |
For 888MEL and A2058 cells, cobimetinib (GDC-0973) has EC50 values of 0.2 M and 10 M, respectively. Treatment of melanoma cells with EC50 concentrations of MEK and PI3K inhibitors (888MEL: 0.05 μM GDC-0973, 2.5 μM GDC-0941; A2058: 2.5 μM GDC-0973, 2.5 μM GDC-0941) lasts for 24 hours. In melanoma with constitutive MAPK activation in A375 cells, mitochondrial OXPHOS regulates the amount of cell death brought on by cobimetinib (100 nM).
The in vitro cellular assay for Cobimetinib racemate 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 racemate 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 to confirm target engagement. The compound's effects on downstream signaling and cell cycle progression are evaluated. Dose-response relationships are established by analyzing cell viability and signaling inhibition across different compound concentrations. |
| 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 racemate are conducted using immunocompromised mice bearing human tumor xenografts, particularly BRAF-mutant melanoma models. Tumor cells are implanted subcutaneously into the flank of nude or SCID mice. When tumors reach a predetermined size, animals are randomized into treatment groups receiving Cobimetinib or vehicle control. Cobimetinib is administered orally due to its oral bioavailability. Tumor volume is measured twice weekly using calipers, and body weight is monitored to assess tolerability. At study endpoint, tumors are harvested for analysis of MEK target engagement, ERK phosphorylation, and markers of proliferation and apoptosis. The compound's antitumor efficacy is evaluated by comparing tumor growth in treated versus control groups. Combination studies with vemurafenib or other agents are also performed. |
| ADME/Pharmacokinetics |
Detailed pharmacokinetic (PK) parameters for Cobimetinib racemate are not extensively documented in publicly available sources. The compound is orally available. Cobimetinib racemate has 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, Cobimetinib 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 including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are available in the primary literature and should be consulted for specific experimental planning.
|
| Toxicity/Toxicokinetics |
Comprehensive toxicological data for Cobimetinib are available from preclinical and clinical studies conducted during its development and FDA approval for melanoma treatment. As a research-grade compound, Cobimetinib racemate 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. The compound should be stored according to the manufacturer's recommendations to maintain stability and prevent degradation. Toxicological data from preclinical and clinical studies are available in the published literature and should be consulted for safety information.
|
| References | |
| Additional Infomation |
See also: Cobimetinib (note moved to).
Cobimetinib racemate is a research compound developed for studying the role of MEK1/2 in the MAPK/ERK signaling pathway and for evaluating MEK inhibition as a therapeutic strategy for cancer. The compound is the racemate of Cobimetinib (GDC-0973, XL518), a potent, selective MEK1 inhibitor with an IC50 of 4.2 nM. Cobimetinib was approved in 2015 for the treatment of BRAF V600-mutated melanoma, used alone or in combination with vemurafenib or with both vemurafenib and atezolizumab. Cobimetinib racemate is widely used in preclinical research to explore the therapeutic potential of MEK inhibition in oncology. Cobimetinib racemate is available from various chemical suppliers for research purposes. Its utility lies in its ability to inhibit MEK1/2 and probe the role of the MAPK/ERK pathway in cancer. |
| Molecular Formula |
C21H21F3IN3O2
|
|
|---|---|---|
| Molecular Weight |
531.31
|
|
| Exact Mass |
531.063
|
|
| CAS # |
934662-91-6
|
|
| Related CAS # |
Cobimetinib;934660-93-2;Cobimetinib hemifumarate;1369665-02-0;Cobimetinib (R-enantiomer);934660-94-3;Cobimetinib-13C6 racemate
|
|
| PubChem CID |
51038893
|
|
| Appearance |
White to off-white solid
|
|
| 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 |
0
|
|
| SMILES |
O=C(N1CC(C2CCCCN2)(O)C1)C1C(NC2C(F)=CC(I)=CC=2)=C(F)C(F)=CC=1
|
|
| InChi Key |
BSMCAPRUBJMWDF-UHFFFAOYSA-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
|
|
| Chemical Name |
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-(3-hydroxy-3-piperidin-2-ylazetidin-1-yl)methanone
|
|
| Synonyms |
|
|
| 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 (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.71 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 (4.71 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 (4.71 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.
 |
|---|
 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. |
|---|
 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. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
