| Name | Encorafenib |
| Description | Encorafenib (LGX818) is an orally available mutated BRaf V600E inhibitor(IC50=0.3 nM) with potential antineoplastic activity. |
| Cell Research | LGX818 is dissolved in DMSO. A375 is a melanoma cell line that harbors the B-Raf V600E mutation. A375-luc cells engineered to express luciferase is plated to 384-well white clear bottom plates as 1,500 cells/50 μL/well in DMEM containing 10% FBS. Test compounds, dissolved in 100% DMSO at appropriate concentrations, are transferred to the cells by a robotic Pin Tool (100 mL). The cells are incubated for 2 days at 25°C, then 25 μL of BrightGloTM is added to each well and the plates are read by luminescence. The concentration of each compound for 50% inhibition (IC50) is calculated by non-linear regression using XL Fit data analysis software. wild type and V600E B-Raf. |
| Kinase Assay | The Raf kinase activity reaction is started by the addition of 10 μL per well of 2×ATP diluted in assay buffer. After 3 hours (bRaf(V600E)) or 1 hour (c-Raf), the reactions are stopped with the addition of 10 μL of stop reagent (60 mM EDTA). Phosphorylated product is measured using a rabbit anti-p-MEK antibody and the Alpha Screen IgG (ProteinA) detection Kit, by the addition of 30 μL to the well of a mixture of the antibody (1:2000 dilution) and detection beads (1:2000 dilution of both beads) in bead buffer (50 mM Tris, pH 7.5, 0.01% Tween20). The additions are carried out under dark conditions to protect the detection beads from light. A lid is placed on top of the plate and incubated for 1 hour at room temperature, then the luminescence is read on a PerkinElmer Envision instrument. The concentration of each compound for 50% inhibition (IC50) is calculated by non-linear regression using XL Fit data analysis software |
| In vitro | In the A375 (BRAFV600E) human melanoma cell line Encorafenib suppresses phospho-ERK (EC50 = 3 nM) leading to potent inhibition of proliferation (EC50 = 4 nM). No significant activity is observed against a panel of 100 kinases (IC50 > 900 nM) and Encorafenib does not inhibit proliferation of > 400 cell lines expressing wild-type BRAF. Contributing to the high potency of Encorafenib is the extremely slow off-rate from BRAFV600E which is not observed with other RAF inhibitors. In biochemical assays the dissociation half-life is >24 hours which translated into sustained target inhibition in cells following drug wash-out. [1] |
| In vivo | Encorafenib treatment at oral doses as low as 6 mg/kg resulted in strong (75%) and sustained (>24 hours) decrease in phospho-MEK, even following clearance of drug from circulation in single dose PK/PD studies in human melanoma xenograft models (BRAFV600E). Encorafenib induces tumor regression in multiple BRAF mutant human tumor xenograft models grown in immune compromised mice and rats at doses as low as 1 mg/kg. Consistent with the in vitro data, Encorafenib is inactive against BRAF wild-type tumors at doses up to 300 mg/kg bid, with good tolerability and linear increase in exposure. Efficacy is also achieved in a more disease-relevant spontaneous metastatic melanoma and a model of melanoma brain metastasis. Encorafenib is a potent and selective RAF kinase inhibitor with unique biochemical properties that contribute to an excellent pharmacological profile. [1] |
| Storage | keep away from direct sunlight | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| Solubility Information | 10% DMSO+40% PEG300+5% Tween 80+45% Saline : 9.3 mg/mL (17.22 mM), Suspension. Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : 93 mg/mL (172.2 mM)
DMSO : 45 mg/mL (83.33 mM)
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| Keywords | inhibit | LGX 818 | Raf kinases | Raf | LGX-818 | Encorafenib | Inhibitor |
| Inhibitors Related | Regorafenib monohydrate | Doramapimod | Vemurafenib | Sulindac sulfide | Sorafenib | Regorafenib | Dabrafenib | Sorafenib tosylate | PLX-4720 | LY3009120 | Pelitinib | GW 441756 |
| Related Compound Libraries | Pain-Related Compound Library | Bioactive Compound Library | Kinase Inhibitor Library | Drug Repurposing Compound Library | Inhibitor Library | FDA-Approved Drug Library | Anti-Cancer Approved Drug Library | Bioactive Compounds Library Max | Anti-Cancer Drug Library | Anti-Cancer Active Compound Library |
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