Avutometinib (Synonyms: Ro 5126766; CH5126766)

Name: Avutometinib
Brand: MedChemExpress
SKU: HY-18652
Rating: 5.0 (3 reviews)

Cat. No.: HY-18652 Purity: 99.02%: FAQs
Data Sheet SDS COA Handling Instructions

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Avutometinib (Ro 5126766) is a first-in-class dual MEK/RAF inhibitor that allosterically inhibits BRAF^V600E, CRAF, MEK, and BRAF (IC₅₀: 8.2, 56, 160 nM, and 190 nM, respectively).

For research use only. We do not sell to patients.

Avutometinib Chemical Structure

CAS No. : 946128-88-7

Size	Price	Stock	Quantity
Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO ready for reconstitution	USD 160	In-stock	Estimated Time of Arrival: December 31
Solution
10 mM * 1 mL in DMSO	USD 160	In-stock	Estimated Time of Arrival: December 31
Solid
5 mg	USD 154	In-stock	Estimated Time of Arrival: December 31
10 mg	USD 242	In-stock	Estimated Time of Arrival: December 31
50 mg	USD 748	In-stock	Estimated Time of Arrival: December 31
100 mg	USD 1045	In-stock	Estimated Time of Arrival: December 31
200 mg		Get quote
500 mg		Get quote

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Customer Review

Based on 3 publication(s) in Google Scholar

Other Forms of Avutometinib:

Avutometinib potassium Get quote

3 Publications Citing Use of MCE Avutometinib

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BRaf c-Raf Raf

Biological Activity
Protocol
Purity & Documentation
References
Customer Review

Description

IC₅₀ & Target^[1]

MEK

160 nM (IC₅₀)

BRaf^V600E

8.2 nM (IC₅₀)

Braf

190 nM (IC₅₀)

CRAF

56 nM (IC₅₀)

Cellular Effect

Cell Line	Type	Value	Description	References
A549	IC₅₀	1.24 μM Compound: 3; RO5126766	Antiproliferative activity against human A549 cells harboring KRAS G12S mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay Antiproliferative activity against human A549 cells harboring KRAS G12S mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay	[PMID: 32305784]
C32	ED₅₀	0.09 mg/kg Compound: 1, CH5126766/RO5126766	Antitumor activity against human C32 cells xenografted in po dosed BALB-nu/nu mouse assessed as tumor growth inhibition administered qd for 11 days Antitumor activity against human C32 cells xenografted in po dosed BALB-nu/nu mouse assessed as tumor growth inhibition administered qd for 11 days	[PMID: 24900832]
HCT-116	IC₅₀	0.053 μM Compound: 3; RO5126766	Antiproliferative activity against human HCT116 cells harboring KRAS G13D mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay Antiproliferative activity against human HCT116 cells harboring KRAS G13D mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay	[PMID: 32305784]
HCT-116	IC₅₀	277 nM Compound: 1; VS6766	Antiproliferative activity against human HCT-116 cells harboring NRAS G13D mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay Antiproliferative activity against human HCT-116 cells harboring NRAS G13D mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay	[PMID: 35849914]
HCT-116	IC₅₀	40 nM Compound: 1, CH5126766/RO5126766	Inhibition of human HCT116 cell growth after 96 hrs by counting kit-8 analysis Inhibition of human HCT116 cell growth after 96 hrs by counting kit-8 analysis	[PMID: 24900832]
HL-60	IC₅₀	0.006 μM Compound: 3; RO5126766	Antiproliferative activity against human HL60 cells harboring NRAS K61L mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay Antiproliferative activity against human HL60 cells harboring NRAS K61L mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay	[PMID: 32305784]
L02	IC₅₀	17.27 μM Compound: 3; RO5126766	Cytotoxicity against human HL7702 cells assessed as reduction in cell viability after 96 hrs by Celltiter-Glo assay Cytotoxicity against human HL7702 cells assessed as reduction in cell viability after 96 hrs by Celltiter-Glo assay	[PMID: 32305784]
MDA-MB-231	IC₅₀	0.17 μM Compound: 3; RO5126766	Antiproliferative activity against human MDA-MB-231 cells harboring KRAS G13D/BRAF G464V mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay Antiproliferative activity against human MDA-MB-231 cells harboring KRAS G13D/BRAF G464V mutant assessed as inhibition of cell viability after 96 hrs by Celltiter-Glo assay	[PMID: 32305784]
MIA PaCa-2	IC₅₀	40 nM Compound: 1; VS6766	Antiproliferative activity against human MIA PaCa-2 cells harboring NRAS G12C mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay Antiproliferative activity against human MIA PaCa-2 cells harboring NRAS G12C mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay	[PMID: 35849914]
SK-MEL-2	IC₅₀	28 nM Compound: 1; VS6766	Antiproliferative activity against human SK-MEL-2 cells harboring NRAS Q61R mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay Antiproliferative activity against human SK-MEL-2 cells harboring NRAS Q61R mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay	[PMID: 35849914]
SK-MEL-28	IC₅₀	65 nM Compound: 1; VS6766	Antiproliferative activity against human SK-MEL-28 cells harboring BRAF V600E mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay Antiproliferative activity against human SK-MEL-28 cells harboring BRAF V600E mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay	[PMID: 35849914]
SW480	IC₅₀	46 nM Compound: 1; VS6766	Antiproliferative activity against human SW480 cells harboring NRAS G12V mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay Antiproliferative activity against human SW480 cells harboring NRAS G12V mutant assessed as cell growth inhibition measured after 72 hrs by WST-8 assay	[PMID: 35849914]
Vero	IC₅₀	> 50 μM Compound: 3; RO5126766	Cytotoxicity against African green monkey Vero cells assessed as reduction in cell viability after 96 hrs by Celltiter-Glo assay Cytotoxicity against African green monkey Vero cells assessed as reduction in cell viability after 96 hrs by Celltiter-Glo assay	[PMID: 32305784]

In Vitro

Avutometinib (Ro 5126766) is an allosteric inhibitor that binds directly to MEK and prevents its phosphorylation by RAF through the formation of a stable RAF-MEK complex. Ro 5126766 inhibits both the phosphorylation of MEK by RAF and the activation of ERK by MEK. In cell-free MEK and RAF kinase assays, Avutometinib effectively inhibits activation of ERK2 by MEK1 with an IC₅₀ of 160 nM (SD=±0.043) and inhibits the phosphorylation of MEK1 protein by BRAF (IC₅₀=190 nM, SD=±0.003), BRAF^V600E (IC₅₀=8.2 nM, SD=±0.0015), and CRAF (IC₅₀=56 nM, SD=±0.016). Avutometinib effectively inhibits both MEK and ERK phosphorylation in a panel of human tumor cell lines including KRAS/HRAS and BRAF mutant cell lines and KRAS/HRAS and BRAF wild-type cells^[1]. In order to investigate whether the mevalonate pathway affects the sensitivity to MEK inhibitors, human breast cancer MDA-MB-231 cells harboring KRAS and BRAF mutations are treated Avutometinib, with or without statins, which inhibits HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. The combined treatment of Avutometinib with XU 62-320 demonstrates more significant reduction in cell growth in a dose-dependent manner than the single treatment of Avutometinib. The marked combined effects of Avutometinib at 40 nM and XU 62-320 at 0.3 μM is also confirmed on the suppression of the colony formation of the cells^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

In Vivo

In KRAS-mutant xenograft models, Avutometinib (Ro 5126766) inhibits growth and causes tumor regressions more effectively than another allosteric MEK inhibitor, PD0325901. Preclinical data from a series of human tumor mouse xenograft models indicates an ED₅₀ for Ro 5126766 of 0.03 to 0.23 mg/kg and an ED₉₀ of 0.15 to 1.56 mg/kg. These effective doses are associated with target trough concentrations of 17 to 133 ng/L and 87 to 901 ng/mL, respectively. ^[1]. In this experiment, Avutometinib or PD0325901 is administrated at their maximum tolerated dose (MTD) in the HCT116 model (1.5 and 25 mg/kg, respectively). These doses inhibit pERK and ERK signaling output at similar degrees in the tumors from the drug-treated mice at 4 hours from the first drug administration. Moreover, in HCT116 models, the ED₅₀ for Avutometinib and PD0325901 are 0.056 and 0.80 mg/kg, respectively. Therefore, the doses used for this experiment are 26.8- and 31.3-fold higher doses than the 50% effective doses, respectively. Daily oral administration of either drug causes significant tumor regression of each these tumors. However, whereas inhibition of tumor growth is maintained for the entire 28-day treatment period in Avutometinib-treated mice, tumor models receiving PD0325901 become refractory after 10 days of treatment^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial

Molecular Weight

471.46

Formula

C₂₁H₁₈FN₅O₅S

CAS No.

946128-88-7

Appearance

Solid

Color

White to yellow

SMILES

O=S(NC)(NC1=NC=CC(CC2=C(C)C3=CC=C(OC4=NC=CC=N4)C=C3OC2=O)=C1F)=O

Shipping

Room temperature in continental US; may vary elsewhere.

Storage

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

Solvent & Solubility

In Vitro:

DMSO : 100 mg/mL (212.11 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions

Concentration Solvent Mass	1 mg	5 mg	10 mg

1 mM	2.1211 mL	10.6054 mL	21.2107 mL
5 mM	0.4242 mL	2.1211 mL	4.2421 mL
10 mM	0.2121 mL	1.0605 mL	2.1211 mL

View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Molarity Calculator
Dilution Calculator

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Concentration _(start) × Volume _(start) = Concentration _(final) × Volume _(final)

This equation is commonly abbreviated as: C₁V₁ = C₂V₂

Concentration _(start)

Volume _(start)

Concentration _(final)

Volume _(final)

In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

Protocol 1

Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 5 mg/mL (10.61 mM); Clear solution

This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Protocol 2

Add each solvent one by one: 10% DMSO 90% Corn Oil
Solubility: ≥ 5 mg/mL (10.61 mM); Clear solution

This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 900 μL Corn oil, and mix evenly.
Protocol 3

Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.08 mg/mL (4.41 mM); Clear solution

This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (20.8 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.

In Vivo Dissolution Calculator

Please enter the basic information of animal experiments:

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mg/kg

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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.

Please enter your animal formula composition:

DMSO +

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Saline

Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.

The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).

Calculation results:

Working solution concentration: mg/mL

Method for preparing stock solution: mg drug dissolved in μL DMSO (Stock solution concentration: mg/mL).

The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).

Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.

If the continuous dosing period exceeds half a month, please choose this protocol carefully.

Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.

Purity & Documentation

Purity: 99.02%

Select Batch:

Data Sheet (290 KB) SDS (393 KB)

COA (246 KB) LCMS (92 KB)

Handling Instructions (2659 KB)

References

[1]. Martinez-Garcia M, et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012 Sep 1;18(17):4806-19. [Content Brief]

[2]. Iizuka-Ohashi M, et al. Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells. Oncotarget. 2018 Apr 13;9(28):19597-19612. [Content Brief]

[3]. 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):4050-4060. [Content Brief]

Cell Assay ^[2]	The number of viable cells is assessed with a Cell Counting Kit-8 assay. Human breast cancer MDA-MB-231 cells, human melanoma SK-MEL-28 cells, and human non-small cell lung cancer A549 cells are seeded at a density of 2,000 cells per well in 96-well plates and incubated for 24 h, and then treated with Ro 5126766 (10, 20, 40, and 80 nM) for 72 h. After a further 4 h incubation with the kit reagent, the absorbance at 450 nm of the samples is measured using a multi-plate reader^[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration ^[3]	Mice^[3] Female BALB-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj nu/nu) are given access to standard mouse chow and water ad libitum. A total of 5×10⁶ (HCT116) or 1×10⁷ (Calu-6 and COLO205) tumor cells per mouse are injected subcutaneously into the right flank of the 7- to 9-week-old mice. When tumor volume reaches to 200 mm³ (day 0), the mice are randomized and vehicle [5% DMSO and 10% 2-hydroxypropyl-β-cyclodextrin (HPCD) solution in distilled water], Avutometinib (1.5 mg/kg or 2.0 mg/kg) or PD0325901 (25 mg/kg) is administered orally once a day. Drugs are administrated at the maximum tolerated dose (MTD). Tumor growth inhibition (TGI) is calculated. The value of the 50% effective dose (ED₅₀) for each compound is calculated^[3]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
References	[1]. Martinez-Garcia M, et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012 Sep 1;18(17):4806-19. [Content Brief] [2]. Iizuka-Ohashi M, et al. Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells. Oncotarget. 2018 Apr 13;9(28):19597-19612. [Content Brief] [3]. 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):4050-4060. [Content Brief]

Complete Stock Solution Preparation Table

Optional Solvent	Concentration Solvent Mass	1 mg	5 mg	10 mg	25 mg

DMSO	1 mM	2.1211 mL	10.6054 mL	21.2107 mL	53.0268 mL
	5 mM	0.4242 mL	2.1211 mL	4.2421 mL	10.6054 mL
	10 mM	0.2121 mL	1.0605 mL	2.1211 mL	5.3027 mL
	15 mM	0.1414 mL	0.7070 mL	1.4140 mL	3.5351 mL
	20 mM	0.1061 mL	0.5303 mL	1.0605 mL	2.6513 mL
	25 mM	0.0848 mL	0.4242 mL	0.8484 mL	2.1211 mL
	30 mM	0.0707 mL	0.3535 mL	0.7070 mL	1.7676 mL
	40 mM	0.0530 mL	0.2651 mL	0.5303 mL	1.3257 mL
	50 mM	0.0424 mL	0.2121 mL	0.4242 mL	1.0605 mL
	60 mM	0.0354 mL	0.1768 mL	0.3535 mL	0.8838 mL
	80 mM	0.0265 mL	0.1326 mL	0.2651 mL	0.6628 mL
	100 mM	0.0212 mL	0.1061 mL	0.2121 mL	0.5303 mL

Avutometinib Related Classifications

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Do most proteins show cross-species activity?
Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

Avutometinib946128-88-7Ro 5126766 CH5126766Ro5126766Ro-5126766CH5126766CH 5126766CH-5126766MEKRafMitogen-activated protein kinase kinaseMAPKKMAP2KRaf kinasesInhibitorinhibitorinhibit

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Avutometinib (Synonyms: Ro 5126766; CH5126766)

Customer Review

Other Forms of Avutometinib:

Avutometinib Related Antibodies

3 Publications Citing Use of MCE Avutometinib

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•Related Screening Libraries:

•Related Small Molecules:

•Related Proteins:

View All MEK Isoform Specific Products:

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Biological Activity

Protocol

Purity & Documentation

References

Customer Review

Avutometinib Related Antibodies

Molarity Calculator

Dilution Calculator

Complete Stock Solution Preparation Table

Avutometinib Related Classifications

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