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Purity: ≥98%
Lifirafenib (formerly BGB-283, Beigene-283) is a potent inhibitor of the RAF kinases and EGFR in biochemical assays with IC50 values of 23, 29 and 495 nM for the recombinant BRAFV600E kinase domain, EGFR and EGFR T790M/L858R mutant respectively. BGB-283 is presently going through clinical trials. In vitro, ERK phosphorylation and cell proliferation triggered by BRAF(V600E) are strongly suppressed by BGB-283. It exhibits preferential inhibition of cancer cell proliferation with BRAF(V600E) and EGFR mutation/amplification, as well as selective cytotoxicity. Effectively blocking EGFR reactivation and EGFR-mediated cell proliferation in BRAF(V600E) colorectal cancer cell lines, BGB-283. In vivo, BGB-283 treatment causes both primary human colorectal tumor xenografts and cell line-derived tumors with the BRAF(V600E) mutation to exhibit dose-dependent inhibition of tumor growth, along with partial and total tumor regressions. Based on these results, BGB-283 may be a useful antitumor medication for the treatment of colorectal cancer with the BRAF(V600E) mutation.
| Targets |
EGFR (IC50 = 29 nM); BRafV600E (IC50 = 23 nM); EGFRL858R/T790M (IC50 = 495 nM)
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| ln Vitro |
BGB-283 strongly suppresses ERK phosphorylation and cell proliferation that is triggered by BRAFV600E in vitro. It exhibits preferentially inhibiting the growth of cancer cells with EGFR mutation/amplification and BRAFV600E mutation/amplification, as well as selective cytotoxicity. BGB-283 efficiently suppresses the reactivation of EGFR and EGFR-mediated cell proliferation in colorectal cancer cell lines BRAFV600E. It exhibits specific cytotoxicity against cell lines with EGFR or BRAFV600E mutations. In A431 cells, BGB-283 dose-dependently blocks the EGFR autophosphorylation on Tyr1068 caused by EGF. It has been demonstrated that BGB-283 can inhibit the feedback activation of EGFR signaling and achieve sustained inhibition of pERK in WiDr colorectal cancer cells[1].
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| ln Vivo |
In vivo, BGB-283 treatment causes both primary human colorectal tumor xenografts and cell line-derived tumors with the BRAFV600E mutation to exhibit dose-dependent inhibition of tumor growth along with partial and total tumor regressions. In xenograft models of colorectal cancer with the BRAF(V600E) mutation, such as HT29, Colo205, and two primary tumor xenografts, BGB-283 exhibits a high degree of efficacy. Furthermore, BGB-283 exhibits remarkable effectiveness in a WiDr xenograft model, demonstrating that BRAF inhibition triggers EGFR reactivation. In HCC827, but not in A431 xenograft, BGB-283 causes tumor regression. In WiDr tumor xenografts, BGB-283 exhibits strong antitumor activity and inhibits the phosphorylation of both EGFR and ERK1/2. Unlike vemurafenib, BGB-283 does not cause EGFR feedback activation. BGB-283 potently suppresses DUSP6 expression and the phosphorylation of MEK and ERK in vivo at repeated doses. Regarding AKT phosphorylation, there is no discernible difference[1].
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| Enzyme Assay |
In biochemical assays, lifafenib (BGB-283) inhibits EGFR and RAF kinases with IC50 values of 23, 29, and 495 nM for EGFR, EGFR T790M/L858R mutant, and recombinant BRAFV600E kinase domain. Using time-resolved fluorescence-resonance energy transfer (TR-FRET) assays, compounds were examined for their ability to inhibit the activity of EGFR kinase in WT and RAF. For RAF kinases, MEK1 (K97R) was employed as a substrate, and for EGFR, a biotinylated peptide substrate (61TK0BLC, CisBio Bioassys) was utilized. A final concentration of 100 mol/L of ATP and kinase substrates were added to the kinase after 60 to 120 minutes of serial compound dilution incubation at room temperature (RT). According to the manufacturer's instructions (CisBio Bioassays), the reaction was stopped with an equal volume of stop/detection solution. Once the plates were sealed and incubated at room temperature for two hours, the PHERAstar FS plate reader (BMG Labtech) was used to record the TR-FRET signals, which are the ratio of fluorescence emission at 665 nm over emission at 620 nm with excitation at 337 nm wavelength. Life Technologies used their standard assays at Km concentration of ATP for perspective kinases to screen BGB-283 for activity in a panel of 277 kinases at a fixed concentration of 10 μmol/L. The kinases exhibiting >80% inhibition at 10 μmol/L BGB-283 were then identified by calculating their IC50.
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| Cell Assay |
For each cell line, the number of cells seeded per well of a 96-well plate is optimized to guarantee logarithmic growth throughout the three-day treatment period. Following a 16-hour attachment period, duplicate cells are subjected to a 10-point dilution series. A volume of CellTiter-Glo reagent equal to the volume of cell culture medium in each well is added after the compound has been exposed for three days. After mixing the mixture for two minutes on an orbital shaker to allow the cells to lyse, the mixture is left to develop and stabilize the luminescent signal for ten minutes at room temperature. The luminosity signal is quantified.
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| Animal Protocol |
Mice: Mice are randomized to treatment groups when the average tumor size reaches 110 to 200 mm3. Treatments consist of oral gavage (p.o.) with vehicle alone or 2.5 to 30 mg/kg of BGB-283 administered twice daily or once daily. Mice given either cetuximab (40 mg/kg twice weekly) or erlotinib (100 mg/kg qd) are used as controls. Erlotinib and ligofenib (BGB-283) are combined to form a homogenous suspension at the required concentration in 0.5% (w/v) methylcellulose in purified water. Before administering, the injection solution for cetuximab is diluted with saline.
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| References |
| Molecular Formula |
C25H17F3N4O3
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| Molecular Weight |
478.42
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| Exact Mass |
478.13
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| Elemental Analysis |
C, 62.76; H, 3.58; F, 11.91; N, 11.71; O, 10.03
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| CAS # |
1446090-79-4
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| Related CAS # |
rel-Lifirafenib;1446090-77-2
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| Appearance |
Solid powder
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| SMILES |
C1CC(=O)NC2=NC=CC(=C21)OC3=CC4=C(C=C3)O[C@H]5[C@@H]4[C@@H]5C6=NC7=C(N6)C=C(C=C7)C(F)(F)F
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| InChi Key |
NGFFVZQXSRKHBM-FKBYEOEOSA-N
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| InChi Code |
InChI=1S/C25H17F3N4O3/c26-25(27,28)11-1-4-15-16(9-11)31-24(30-15)21-20-14-10-12(2-5-17(14)35-22(20)21)34-18-7-8-29-23-13(18)3-6-19(33)32-23/h1-2,4-5,7-10,20-22H,3,6H2,(H,30,31)(H,29,32,33)/t20-,21-,22-/m0/s1
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| Chemical Name |
5-[[(1R,1aS,6bR)-1-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-5-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0902 mL | 10.4511 mL | 20.9021 mL | |
| 5 mM | 0.4180 mL | 2.0902 mL | 4.1804 mL | |
| 10 mM | 0.2090 mL | 1.0451 mL | 2.0902 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03905148 | Active Recruiting |
Drug: Lifirafenib Drug: mirdametinib |
Solid Tumor, Adult | BeiGene | May 1, 2019 | Phase 1 |
BGB-283, a compound designed for inhibiting oncogenic BRAF. A, chemical structure of BGB-283. B, the crystal structure of BGB-283 bound to BRAFV600E. Dashed lines are hydrogen bonds.Mol Cancer Ther.2015 Oct;14(10):2187-97. |
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BGB-283 potently inhibited ERK phosphorylation and EGFR activity.Mol Cancer Ther.2015 Oct;14(10):2187-97. |
BGB-283 selectively inhibited proliferation of cancer cells harboringBRAFV600E andEGFRmutations. Antiproliferative effect of BGB-283 (A) and PLX4032 (B) following a 3D exposure across a panel of human cancer cell lines determined by the CellTiter-Glo assay.Mol Cancer Ther.2015 Oct;14(10):2187-97. |
BGB-283 inhibited tumor growth in both cell line–derived and primary human colorectal cancer xenograft models harboringBRAFV600Emutation.Mol Cancer Ther.2015 Oct;14(10):2187-97. |
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