Ro 5126766

Ro 5126766 (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).

Product information

CAS Number: 946128-88-7

Molecular Weight: 471.46

Formula: C21H18FN5O5S

Synonym:

CH5126766

Chemical Name: 3-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-chromen-2-one

Smiles: CC1C2=CC=C(C=C2OC(=O)C=1CC1=CC=NC(NS(=O)(=O)NC)=C1F)OC1=NC=CC=N1

InChiKey: LMMJFBMMJUMSJS-UHFFFAOYSA-N

InChi: InChI=1S/C21H18FN5O5S/c1-12-15-5-4-14(31-21-25-7-3-8-26-21)11-17(15)32-20(28)16(12)10-13-6-9-24-19(18(13)22)27-33(29,30)23-2/h3-9,11,23H,10H2,1-2H3,(H,24,27)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO : 100 mg/mL (212.11 mM; Need ultrasonic)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

Ro 5126766 (RO5126766) 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, Ro 5126766 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), BRAFV600E (IC50=8.2 nM, SD=±0.0015), and CRAF (IC50=56 nM, SD=±0.016). Ro 5126766 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. 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 Ro 5126766 (CH5126766), with or without statins, which inhibits HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. The combined treatment of Ro 5126766 with XU 62-320 demonstrates more significant reduction in cell growth in a dose-dependent manner than the single treatment of Ro 5126766. The marked combined effects of Ro 5126766 at 40 nM and XU 62-320 at 0.3 μM is also confirmed on the suppression of the colony formation of the cells.

In Vivo:

In KRAS-mutant xenograft models, Ro 5126766 (RO5126766) 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. In this experiment, Ro 5126766 (CH5126766) 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 Ro 5126766 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 Ro 5126766-treated mice, tumor models receiving PD0325901 become refractory after 10 days of treatment.

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.
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.
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.

Products are for research use only. Not for human use.