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Purity: ≥98%
| Targets |
MEK1 (IC50 = 4.2 nM)
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|---|---|
| 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 lose viability, inhibit certain pathways, and undergo more apoptosis when combined with GDC-0941.[1]
Across all BRAFV600E lines, coadministration of GDC-0973 and vemurafenib significantly increases decreased levels of GLUT-1 on the cellular membrane.[2] |
| 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.[1]
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.[2] |
| 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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| Cell Assay |
For 888MEL and A2058 cells, the EC50 concentrations of cobimetinib (GDC-0973) are 0.2 M and 10 M, respectively. EC50 concentrations of MEK and PI3K inhibitors are applied to melanoma cells for 24 hours (888MEL: 0.05 M GDC-0973, 2.5 M GDC-0941; A2058: 2.5 M GDC-0973, 2.5 M GDC-0941). Cell death brought on by cobimetinib (100 nM) in melanoma with constitutive MAPK activation in A375 cells is restricted by mitochondrial OXPHOS.
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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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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (Tmax) was 2.4 (range:1–24) hours, geometric mean steady-state AUC0-24h was 4340 ng∙h/mL (61% CV) and Cmax was 273 ng/mL (60% CV). The absolute bioavailability of COTELLIC was 46% (90% CI: 40%, 53%) in healthy subjects. A high‐fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on cobimetinib AUC and Cmax after a single 20 mg COTELLIC was administered to healthy subjects. Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine (with 1.6% as unchanged drug). The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis. Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean apparent clearance (CL/F) was 13.8 L/h (61% CV). Metabolism / Metabolites Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed. Biological Half-Life Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
Elevations in serum aminotransferase and alkaline phosphatase levels are common during vemurafenib therapy and are even more common when it is combined with cobimetinib, abnormal liver tests occurring in 26% to 70% of treated patients and ALT values rising above 5 times the upper limit of the normal range (ULN) in 6% to 12%. Instances of clinically apparent liver injury with jaundice have also been reported during the clinical trials of cobimetinib and vemurafenib therapy, but the clinical features, course and outcomes of these episodes have not been described in detail. At least one instance of hepatocellular injury with jaundice was included in the initial safety review of cobimetinib. The MAPK pathway inhibitors as a class are often associated with transient serum enzyme elevations and more rarely with instances of clinically apparent liver injury, but the clinical features have not been described and the association with cobimetinib not clearly defined. The rate of clinically significant liver injury and hepatic failure associated with protein kinase inhibitors is increased in patients with preexisting cirrhosis or hepatic impairment due to liver tumor burden. Likelihood score: D (possible cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of cobimetinib during breastfeeding. Because cobimetinib is 90% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 44 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during cobimetinib therapy and for 2 weeks after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. |
| References | |
| Additional Infomation |
Pharmacodynamics
Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors become BRAF-inhibitor resistant due to reactivation of MAPK signaling. BRAF-inhibitor-resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK. |
| Molecular Formula |
C21H21F3IN3O2
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|---|---|
| Molecular Weight |
531.318
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| Exact Mass |
531.063
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| Elemental Analysis |
C, 47.47; H, 3.98; F, 10.73; I, 23.88; N, 7.91; O, 6.02
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| CAS # |
934660-93-2
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| Related CAS # |
Cobimetinib hemifumarate;1369665-02-0;Cobimetinib racemate;934662-91-6;Cobimetinib (R-enantiomer);934660-94-3
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| PubChem CID |
16222096
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| Appearance |
white solid powder
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| Density |
1.7±0.1 g/cm3
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| Boiling Point |
565.9±50.0 °C at 760 mmHg
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| Flash Point |
296.1±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.662
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| LogP |
5.96
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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 |
C(N1CC([C@H]2NCCCC2)(O)C1)(C1=CC=C(F)C(F)=C1NC1C=CC(I)=CC=1F)=O
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| InChi Key |
BSMCAPRUBJMWDF-KRWDZBQOSA-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-/m0/s1
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| Chemical Name |
[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 |
cobimetinib; Cotellic; XL518; XL 518; XL-518; GDC0973; GDC-0973; GDC 0973;RG 7420; RG-7420; RG7420
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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 |
| 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 (4.71 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: ≥ 2.5 mg/mL (4.71 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 5: 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 | 9.4105 mL | 18.8210 mL | |
| 5 mM | 0.3764 mL | 1.8821 mL | 3.7642 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03108131 | Active Recruiting |
Drug: Atezolizumab Drug: Cobimetinib |
Rare Lesion Appendix Adenocarcinoma |
M.D. Anderson Cancer Center | April 7, 2017 | Phase 2 |
| NCT03175432 | Active Recruiting |
Drug: Atezolizumab Drug: Cobimetinib |
Intracranial Melanoma BRAF V600 Wild Type |
M.D. Anderson Cancer Center | June 15, 2017 | Phase 2 |
| NCT02036086 | Active Recruiting |
Drug: Vemurafenib Drug: Cobimetinib |
Melanoma | Sunnybrook Health Sciences Centre |
August 2015 | Phase 2 |
| NCT03625141 | Active Recruiting |
Drug: Cobimetinib Drug: Atezolizumab |
Metastatic Melanoma | Hoffmann-La Roche | December 13, 2018 | Phase 2 |
| NCT02908672 | Active Recruiting |
Drug: Atezolizumab Drug: Cobimetinib |
Melanoma | Hoffmann-La Roche | January 13, 2017 | Phase 3 |
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. |
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. |
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