RO5126766(CH5126766) (Synonyms: CH5126766, VS-6766) |
| Catalog No.GC12406 |
RO5126766(CH5126766) (CH5126766) is a first-in-class dual MEK/RAF inhibitor that allosterically inhibits BRAFV600E, CRAF, MEK, and BRAF (IC50: 8.2, 56, 160 nM, and 190 nM, respectively).
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 946128-88-7
Sample solution is provided at 25 µL, 10mM.
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RO5126766 (CH5126766) is a first-in-class dual inhibitor of Raf/MEK [1].
The RAS/RAF/MEK/ERK signaling pathway is an important signal transduction system and participates in cell differentiation, movement, division and death. Activated Ras activates RAF kinase, which then phosphorylates and activates MEK (MEK1 and MEK2) [1]. The mutations in BRAF, RAS, and NF1 are associated with many human tumors [2].
RO5126766 (CH5126766) is a first-in-class dual Raf/MEK inhibitor. In cell-free kinase assays, CH5126766 effectively inhibited the phosphorylation of MEK1 protein by RAF and the activation of ERK2 protein by MEK1 with IC50 values of 0.0082-0.056 and 0.16 μM, respectively. In NCI-H460 (KRAS Q61H) human lung large cell carcinoma cell line, RO5126766 induced cell-cycle inhibitor p27Kip1 protein expression and caused G1 arrest. In HCT116 KRAS-mutant colorectal cancer cells, RO5126766 CH5126766 completely inhibited the phosphorylation of MEK and ERK [2].
In Japanese patients with advanced solid tumors, RO5126766 exhibited the maximum tolerable dose (MTD) of 2.25 mg/day once daily [1]. In a HCT116 (G13D KRAS) mouse xenograft model, RO5126766 (1.5 mg/kg) inhibited pERK and ERK signaling and exhibited ED50 value of 0.056 mg/kg [2].
References:
[1]. Honda K, Yamamoto N, Nokihara H, et al. Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 2013, 72(3): 577-584.
[2]. Ishii N, Harada N, Joseph EW, et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res, 2013, 73(13): 4050-4060.
| Kinase experiment [1]: | |
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Kinase assays |
Inhibition of MEK1 was evaluated by a coupled assay with active MEK1 (MEK1 S218E/S222E) and unactive dephosphorylated ERK2 (MAP kinase 2/Erk 2). The phosphorylation of a fluorescent-labeled peptide substrate (FAM-Erktide, IPTTPITTTYFFFK-5FAM-COOH) by ERK2 was quantified by using the IMAP FP Screening Express Kit. |
| Cell experiment [1]: | |
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Cell lines |
HCT116 cell line |
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Preparation method |
This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
|
Reacting condition |
Cells were treated with 250 nmol/L CH5126766 in 0.1% DMSO for 2 hours. |
|
Applications |
CH5126766 binding could cause MEK to adopt a conformation in which MEK could not be phosphorylated by RAF, resulting in the formation of a stable MEK/RAF complex and inhibition of RAF kinase. Consistent with this mechanism, CH5126766 did not induce MEK phosphorylation. |
| Animal experiment [1]: | |
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Animal models |
HCT116 mouse xenograft model |
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Dosage form |
CH5126766 was dissolved in distilled water containing 5% DMSO and 10% HPCD. Drugs were administrated orally once a day at 1.5 mg/kg. |
|
Application |
Daily oral administration of CH5126766 caused significant tumor regression in HCT116 mouse xenograft model. |
|
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
|
References: [1] Ishii N, et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res. 2013 Jul 1;73(13):4050-60. | |
| Cas No. | 946128-88-7 | SDF | |
| Synonyms | CH5126766, VS-6766 | ||
| Canonical SMILES | CC(C1=C(O2)C=C(OC3=NC=CC=N3)C=C1)=C(C2=O)CC4=C(F)C(NS(NC)(=O)=O)=NC=C4 | ||
| Formula | C21H18FN5O5S | M.Wt | 471.46 |
| Solubility | Soluble in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1211 mL | 10.6054 mL | 21.2107 mL |
| 5 mM | 424.2 μL | 2.1211 mL | 4.2421 mL |
| 10 mM | 212.1 μL | 1.0605 mL | 2.1211 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 13 reference(s) in Google Scholar.)
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