LGX818

RAF inhibitor,potent and selective CAS# 1269440-17-6

LGX818

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LGX818

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Chemical Properties of LGX818

Cas No. 1269440-17-6 SDF Download SDF
PubChem ID 50922675 Appearance Powder
Formula C22H27ClFN7O4S M.Wt 540.01
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Encorafenib
Solubility DMSO : 50 mg/mL (92.59 mM; Need ultrasonic)
Chemical Name methyl N-[(2S)-1-[[4-[3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate
SMILES CC(C)N1C=C(C(=N1)C2=CC(=CC(=C2F)NS(=O)(=O)C)Cl)C3=NC(=NC=C3)NCC(C)NC(=O)OC
Standard InChIKey CMJCXYNUCSMDBY-ZDUSSCGKSA-N
Standard InChI InChI=1S/C22H27ClFN7O4S/c1-12(2)31-11-16(17-6-7-25-21(28-17)26-10-13(3)27-22(32)35-4)20(29-31)15-8-14(23)9-18(19(15)24)30-36(5,33)34/h6-9,11-13,30H,10H2,1-5H3,(H,27,32)(H,25,26,28)/t13-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of LGX818

DescriptionEncorafenib (LGX818) is a highly potent inhibitor of RAF with selective anti-proliferative and apoptotic activity in cells expressing B-RAF(V600E) with EC50 of 4 nM.
TargetsB-RAF(V600E)    
IC504 nM (EC50)     

Protocol

Kinase Assay [1]
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

Cell Assay [1]
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.

References:
[1]. Compounds and compositions as protein kinase inhibitors . Patent WO 2011025927 A1 [2]. Li Z, et al. Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44.

LGX818 Dilution Calculator

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Preparing Stock Solutions of LGX818

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8518 mL 9.2591 mL 18.5182 mL 37.0364 mL 46.2954 mL
5 mM 0.3704 mL 1.8518 mL 3.7036 mL 7.4073 mL 9.2591 mL
10 mM 0.1852 mL 0.9259 mL 1.8518 mL 3.7036 mL 4.6295 mL
50 mM 0.037 mL 0.1852 mL 0.3704 mL 0.7407 mL 0.9259 mL
100 mM 0.0185 mL 0.0926 mL 0.1852 mL 0.3704 mL 0.463 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on LGX818

LGX818 is a potent and selective inhibitor of RAF kinase with EC50 value of 3nM in A375 cells [1].

The V600E mutation of B-Raf in the kinase domain results in constitutive activation of B-Raf and promotes cancer development. LGX818 is a RAF kinase inhibitor targeting V600E mutant B-Raf. It has little effect against wild-type BRAF. LGX818 has selective anti-proliferative and apoptotic activity ion in cells expressing BRAFV600E. It shows no significant activity against a panel of 100 kinases and no suppression of cell growth with more than 400 cell lines expressing BRAFV600E. In the A375 human melanoma cell line, LGX818 inhibits the phospho-ERK with EC50 value of 3nM and causes subsequent cell proliferation inhibition with EC50 value of 4nM. In human melanoma xenograft models, oral administration of LGX818 shows strong decrease in phospho-MEK and induces tumor regression [1, 2].

References:
[1] Stuart D D, Li N, Poon D J, et al. Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. Cancer Research, 2012, 72(8 Supplement): 3790.
[2] Huang T, Karsy M, Zhuge J, et al. B-Raf and the inhibitors: from bench to bedside. J Hematol Oncol, 2013, 6(1): 30.

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References on LGX818

A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer.[Pubmed:28363909]

Cancer Discov. 2017 Jun;7(6):610-619.

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAF(V600E) colorectal cancer models. Patients with refractory BRAF(V600)-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kalpha inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610-9. (c)2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539.

Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells.[Pubmed:26586345]

Cancer Lett. 2016 Jan 28;370(2):332-44.

Encorafenib (LGX818) is a new-generation BRAF inhibitor that is under evaluation in clinical trials. However, the underlying mechanism remains to be elucidated. Here we show that LGX818 potently decreased ERK phosphorylation and inhibited proliferation in BRAFV600E melanoma cell lines. Moreover, LGX818 downregulated CyclinD1 in a glycogen synthase kinase 3beta-independent manner and induced cell cycle arrest in the G1 phase, Surprisingly, LGX818 triggered cellular senescence in BRAFV600E melanoma cells, as evidenced by increased beta-galactosidase staining, while no appreciable induction of apoptosis was detected, as determined by Annexin V and propidium iodide staining and immunoblot analysis of caspase-3 processing and poly (ADP-ribose) polymerase cleavage. Increased p27KIP1 expression and retinoblastoma protein activation were detected during LGX818-induced senescence. Additionally, inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 1B by AZ191 reversed LGX818-induced CyclinD1 turnover and senescence. Interestingly, autophagy is triggered through inhibition of the mTOR/70S6K pathway during LGX818-induced senescence. Moreover, autophagy inhibition by pharmacological and genetic regulation attenuates LGX818-induced senescence. Notably, combining LGX818 with autophagy modulators has anti-proliferative effect in LGX818-resistant BRAF mutant melanoma cells. Altogether, we uncovered a mechanism by which LGX818 exerts its anti-tumor activity in BRAFV600E melanoma cells.

Description

Encorafenib (LGX818) is a highly potent BRAF inhibitor with selective anti-proliferative and apoptotic activity in cells expressing BRAFV600E (EC50=4 nM).

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