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RO5126766 (VS-6766)

Cat. No. M10369
RO5126766 (VS-6766) Structure
Synonym:

CH5126766; VS 6766; Avutometinib

Size Price Availability
10mg USD 226  USD226 Custom Synthesis
50mg USD 689  USD689 Custom Synthesis
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Quality Control & Documentation
Biological Activity

RO5126766 (CH5126766, VS 6766) is a first-in-class dual MEK/RAF inhibitor with IC50 values of 8.2 nM, 19 nM, 56 nM and 160 nM for BRAF V600E, BRAF, CRAF and MEK1, respectively. In HCT116 KRAS-mutant colorectal cancer cells, CH5126766 significantly reduces the levels of phospho-MEK and phospho-ERK. CH5126766 inhibits RAF kinase by binding to MEK1, and causes MEK to become a dominant negative inhibitor of RAF. In Raf or RAS-mutant cell lines SK-MEL-28, SK-MEL-2, MIAPaCa-2, SW480, HCT116, and PC3 cells, CH5126766 inhibits cell growth with IC50 of 65, 28, 40, 46, and 277 nM, respectively.

In vivo, RO5126766 (25 mg/kg, p.o.) inhibits ERK signaling output more effectively in an HCT116 (G13D KRAS) mouse xenograft model than a standard MEK inhibitor that induces MEK phosphorylation, and has potent antitumor activity. In the HCT116 (K-ras) and COLO205 (B-raf) mutant xenografts, CH5126766 (0.3 mg/kg) causes significant decreases in [18F]FDG uptake.

Chemical Information
Molecular Weight 471.46
Formula C21H18FN5O5S
CAS Number 946128-88-7
Solubility (25°C) DMSO 90 mg/mL
Storage Powder          -20°C   3 years ;  4°C   2 years
In solvent       -80°C   6 months ;  -20°C   1 month
Conversion of different model animals based on BSA (PMID: 27057123)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Mahiro Iizuka-Ohashi, et al. Oncotarget. Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells

[2] Makoto Wada, et al. PLoS One. The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells

[3] Tetyana Tegnebratt, et al. EJNMMI Res. [18 F]FDG-PET imaging is an early non-invasive pharmacodynamic biomarker for a first-in-class dual MEK/Raf inhibitor, RO5126766 (CH5126766), in preclinical xenograft models

[4] Nobuya Ishii, et al. Cancer Res. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity

[5] Maria Martinez-Garcia, et al. Clin Cancer Res. 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

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Keywords: RO5126766 (VS-6766), CH5126766; VS 6766; Avutometinib supplier, MEK, inhibitors, activators


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