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Cobimetinib

Selective MEK inhibitor CAS# 934660-93-2

Cobimetinib

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Quality Control of Cobimetinib

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Chemical structure

Cobimetinib

3D structure

Chemical Properties of Cobimetinib

Cas No. 934660-93-2 SDF Download SDF
PubChem ID 16222096 Appearance Powder
Formula C21H21F3IN3O2 M.Wt 531.31
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GDC-0973; XL518
Solubility DMSO : ≥ 100 mg/mL (188.21 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone
SMILES C1CCNC(C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O
Standard InChIKey BSMCAPRUBJMWDF-KRWDZBQOSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Cobimetinib

DescriptionCobimetinib is a novel selective MEK inhibitor, and the IC50 value against MEK1 is 4.2 nM.In Vitro:The EC50 values of Cobimetinib (GDC-0973) for 888MEL and A2058 cells are 0.2 μM, 10 μM, respectivelly. Melanoma cells are treated with EC50 concentration 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)[1]. Mitochondrial OXPHOS limits cell death induced by cobimetinib (100 nM) in melanoma with constitutive MAPK activation in A375 cells[4].In Vivo:In the NCI-H2122 KRASG12C mutant non-small cell lung carcinoma (NSCLC) xenograft model, treatment with up to 5 mg/kg Cobimetinib (GDC-0973) lead to moderate TGI and at 10 mg/kg approaches tumor stasis[1]. GDC-0973 and GDC-0941 are administered to A2058 tumor-bearing mice daily (QD) or every third day (Q3D) either as single agents or in combination. The population rate constants associated with tumor growth inhibition for GDC-0973 and GDC-0941 are 0.00102 and 0000651 μM-1 h-1, respectively[2]. Following single doses of GDC-0973 (1, 3, or 10 mg/kg, p.o.) estimated in vivo IC50 values of %pERK decrease based on tumor concentrations in xenograft mice are 0.78 (WM-266-4) and 0.52 μM (A375)[3].

References:
[1]. Hoeflich KP, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012 Jan 1;72(1):210-9. [2]. Choo EF, et al. PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts. Cancer Chemother Pharmacol. 2013 Jan;71(1):133-43. [3]. Wong H, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res. 2012 Jun 1;18(11):3090-9. [4]. Corazao-Rozas P, et al. Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors. Oncotarget. 2016 Feb 29. doi: 10.18632/oncotarget.7790.

Protocol

Animal Administration [3]
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:
[1]. Hoeflich KP, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012 Jan 1;72(1):210-9. [2]. Choo EF, et al. PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts. Cancer Chemother Pharmacol. 2013 Jan;71(1):133-43. [3]. Wong H, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res. 2012 Jun 1;18(11):3090-9. [4]. Corazao-Rozas P, et al. Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors. Oncotarget. 2016 Feb 29. doi: 10.18632/oncotarget.7790.

Cobimetinib Dilution Calculator

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Preparing Stock Solutions of Cobimetinib

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8821 mL 9.4107 mL 18.8214 mL 37.6428 mL 47.0535 mL
5 mM 0.3764 mL 1.8821 mL 3.7643 mL 7.5286 mL 9.4107 mL
10 mM 0.1882 mL 0.9411 mL 1.8821 mL 3.7643 mL 4.7054 mL
50 mM 0.0376 mL 0.1882 mL 0.3764 mL 0.7529 mL 0.9411 mL
100 mM 0.0188 mL 0.0941 mL 0.1882 mL 0.3764 mL 0.4705 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Cobimetinib

Cobimetinib is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) with IC50 value of 0.9 nM [1].
MEK is a kinase enzyme which selectively phosphorylates Ser/Thr and Tyr residues and involved in the mitogen-activated protein kinase (MAPK) signaling pathways that play an important role in regulation of cell proliferation, survival, differentiation, motility and angiogenesis [2].
In a KRAS G13D and B-RAF G464V mutant MDA-MB-231T breast adenocarcinoma cells, Cobimetinib inhibited MEK with IC50 value of 0.2 nM [1]. In pharmacokinetic-pharmacodynamic (PK-PD) model, Cobimetinib showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma [3].
In WM-266-4 xenograft mice, Cobimetinib decreased %pERK in tumor with IC50 values of 0.78 (WM-266-4) and 0.52 mM. Also, Cobimetinib (3.89 mM) increased IC50 value in WM-266-4 mice. In A375 xenograft mice, Cobimetinib (0.3-30 mg/kg) showed antitumor efficacy in a dose-dependent way. Cobimetinib is currently in phase I clinical trials as a potential antitumor agent [3].
References:
[1]. Rice KD, Aay N, Anand NK, et al. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett, 2012, 3(5): 416-421.
[2]. Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol, 2013, 6: 27.
[3]. Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res, 2012, 18(11): 3090-3099.

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References on Cobimetinib

Cobimetinib: inhibiting MEK1/2 in BRAF V600-mutant melanoma.[Pubmed:28112278]

Drugs Today (Barc). 2016 Nov;52(11):593-605.

Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor Cobimetinib. Recently, Cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib. Currently, multiple clinical trials are investigating this drug combination for the treatment of various cancer types (e.g., breast, melanoma, colorectal). In the phase III coBRIM trial, this combination therapy showed improved melanoma response rates and patient progression-free survival when compared to vemurafenib alone. Additionally, toxicities were generally found to be manageable with dose modification or interruption. However, tumor response to BRAF/MEK inhibition, though rapid, is often short-lived as tumors develop resistance to this combination therapy. Therefore, new trials are beginning to investigate the addition of a third targeted agent or immunotherapy in order to increase the durability of treatment response. These trials are already showing promising preliminary results.

Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients.[Pubmed:28052762]

J Hematol Oncol. 2017 Jan 4;10(1):3.

BACKGROUND: Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus Cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies. METHODS: A systematic literature search identified two randomized trials as suitable for indirect comparison: the coBRIM trial of vemurafenib plus Cobimetinib versus vemurafenib and the COMBI-v trial of dabrafenib plus trametinib versus vemurafenib. The comparison followed the method of Bucher et al. and analyzed both efficacy (overall survival [OS], progression-free survival [PFS], and overall response rate [ORR]) and safety outcomes (adverse events [AEs]). RESULTS: The indirect comparison revealed similar efficacy outcomes between both therapies, with no statistically significant difference between therapies for OS (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.68 - 1.30), PFS (HR 1.05, 95% CI 0.79 - 1.40), or ORR (risk ratio [RR] 0.90, 95% CI 0.74 - 1.10). Dabrafenib plus trametinib differed significantly from vemurafenib plus Cobimetinib with regard to the incidence of treatment-related AE (RR 0.92, 95% CI 0.87 - 0.97), any AE grade >/=3 (RR 0.71, 95% CI 0.60 - 0.85) or dose interruption/modification (RR 0.77, 95% CI 0.60 - 0.99). Several categories of AEs occurred significantly more frequently with vemurafenib plus Cobimetinib, while some occurred significantly more frequently with dabrafenib plus trametinib. For severe AEs (grade 3 or above), four occurred significantly more frequently with vemurafenib plus Cobimetinib and no severe AE occurred significantly more frequently with dabrafenib plus trametinib. CONCLUSIONS: This indirect treatment comparison suggested that dabrafenib plus trametinib had comparable efficacy to vemurafenib plus Cobimetinib but was associated with reduced adverse events.

Description

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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