Encorafenib

SKU: orb1300725

Description

Encorafenib (LGX818) is a potent and selective oral inhibitor of the BRAF V600E mutation, with an IC50 of 0.3 nM. It is widely used in preclinical oncology research, demonstrating significant antitumor activity in both in vitro cellular assays and in vivo models of melanoma and colorectal cancer.

Research Area

Pharmacology & Drug Discovery, Signal Transduction

Key Properties

• CAS Number: 1269440-17-6
• MW: 540.01
• Purity: 99.87% (May vary between batches)
• Formula: C₂₂H₂₇ClFN₇O₄S
• SMILES: COC(=O)N[C@@H](C)CNc1nccc(n1)-c1cn(nc1-c1cc(Cl)cc(NS(C)(=O)=O)c1F)C(C)C
• Target: Raf
• Solubility: H2O:< 1 mg/mL (insoluble or slightly soluble);10% DMSO+40% PEG300+5% Tween 80+45% Saline:9.3 mg/mL (17.22 mM);DMSO:257 mg/mL (475.92 mM);Ethanol:93 mg/mL (172.22 mM)

Bioactivity

• Target IC50:
  B-Raf (V600E):0.3 nM
• 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.
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• 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.
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• 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.
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Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Raf, Raf kinases, B-Raf (V600E), Inhibitor, LGX 818, LGX818, LGX-818, Encorafenib, inhibit

Compound Identifiers

PubChem CID

50922675