Encorafenib (LGX818)

Catalog No.S7108

Encorafenib (LGX818) Chemical Structure

Molecular Weight(MW): 540.01

Encorafenib (LGX818) is a highly potent RAF inhibitor with selective anti-proliferative and apoptotic activity in cells expressing B-RAF(V600E) with EC50 of 4 nM. Phase 3.

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Cited by 8 Publications

2 Customer Reviews

  • Whole cell lysates from NRAS- or BRAF-mutant melanoma cells treated with encorafenib or/and binimetinib or DMSO as a control for 24 h were subjected to Western blot analysis to detect pERK, ERK and β-Actin. Experiment shown is a representative of three independent experiments.

    Clin Cancer Res, 2017, 23(20):6203-6214. Encorafenib (LGX818) purchased from Selleck.

    (E) A375 and G361 cells were transfected with GFP-mRFP-LC3 for 24 h, then they were treated the same as in (D) for 4 and 24 h. Images were taken with a confocal microscope.

    Cancer Lett, 2016, 370(2):332-44.. Encorafenib (LGX818) purchased from Selleck.

Purity & Quality Control

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Biological Activity

Description Encorafenib (LGX818) is a highly potent RAF inhibitor with selective anti-proliferative and apoptotic activity in cells expressing B-RAF(V600E) with EC50 of 4 nM. Phase 3.
Features Orally bioavailable RAF-selective inhibitor.
Targets
B-Raf (V600E) [1]
()
In vitro

In the A375 (BRAFV600E) human melanoma cell line LGX818 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 LGX818 does not inhibit proliferation of > 400 cell lines expressing wild-type BRAF. Contributing to the high potency of LGX818 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]
Assay
Methods Test Index PMID
Western blot
p-ERK / ERK / p-MEK / MEK / p-p90RSK / p90RSK; 

PubMed: 29210065     


The expression of MAPK‐related proteins was measured in melanoma cell lines after 24 hr treatment with 1 µM encorafenib and/or 35 nM panobinostat or DMSO carrier control. Arrow indicates phospho‐MEK, * indicates non‐specific band.

BIM / Mcl-1 / Bcl2 / Bcl-xl / NOXA / MITF / c-myc / PARP / Cleaved caspase; 

PubMed: 29210065     


Protein expression of the indicated proteins was measured in melanoma cell lines treated for 24 hr with 1 µM encorafenib and/or 35 nM panobinostat. 

Cyclin D1 / CDC6 / CDK2 ; 

PubMed: 26586345     


A375 and G361 cells were treated with varying concentrations of LGX818 (1, 10 and 100 nM) for 24 h. Protein expressions of CyclinD1, CDC6, CDK2 and GAPDH were analyzed by IB.

p21CIP1 / p27KIP1 / pRb ; 

PubMed: 26586345     


A375 and G361 cells were treated with LGX818 for 0, 1.5, 3, 6, 12, 24, 48, 72 h. IB analysis for p21CIP1, p27KIP1, pRb and GAPDH.

p-mTOR / pp70S6K; 

PubMed: 26586345     


A375 and G361 cells were treated with were treated with varying concentrations of LGX818 (1, 10 and 100 nM) for 24 h. IB analysis for p-mTOR, pp70s6k and GAPDH.

29210065 26586345
Growth inhibition assay
Cell viability; 

PubMed: 26586345     


(A, B) RPMI7951 cells were treated with varying concentrations of Rapa (A) or BEZ235 (B), then they were treated with vehicle or 10 nM LGX818, the inhibition on growth was determined by MTT assay after 24, 48, 72 h. Results represent as the mean ± SEM, **0.001 < p < 0.01, ***p < 0.001

26586345
In vivo LGX818 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). LGX818 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, LGX818 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. LGX818 is a potent and selective RAF kinase inhibitor with unique biochemical properties that contribute to an excellent pharmacological profile. [1]

Protocol

Solubility (25°C)

In vitro DMSO 100 mg/mL (185.18 mM)
Ethanol 100 mg/mL (185.18 mM)
Water Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 540.01
Formula

C22 H27 Cl F N7 O4 S
CAS No. 1269440-17-6
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02834364 Recruiting Drug: Encorafenib|Drug: Binimetinib Relapsed or Refractory Multiple Myeloma|Patients With BRAFV600 E or BRAFV600K Mutation University of Heidelberg Medical Center|Array BioPharma|German Cancer Research Center|Coordinating Centre for Clinical Trials Heidelberg|University Hospital Heidelberg June 2016 Phase 2
NCT02278133 Completed Drug: WNT974|Drug: LGX818|Biological: Cetuximab Metastatic Colorectal Cancer Array BioPharma December 2014 Phase 1|Phase 2
NCT01981187 Completed Drug: LGX818 Solid Tumor|Hematologic Malignancies Array BioPharma January 2014 Phase 2
NCT01909453 Active not recruiting Drug: LGX818|Drug: MEK162|Drug: vemurafenib Melanoma Array BioPharma September 2013 Phase 3
NCT01543698 Active not recruiting Drug: LGX818|Drug: MEK162|Drug: LEE011 Solid Tumors Harboring a BRAF V600 Mutation Array BioPharma May 2012 Phase 1|Phase 2

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Raf Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID