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Purity: ≥98%
PLX7904 (also known as PLX-7904; PB04; PB-04) is a novel potent and selective paradox-breaker B-Raf inhibitor with anticancer activity. It is also known as PLX-7904, PB04, and PB-04. In cells expressing mutant RAS, it blocks BRAFV600E with an IC50 value of less than 5 nM. Its IC50 values are 0.17 μM, 0.53 μM, and 0.16 μM for the two melanoma cell lines (A375 and COLO829) as well as the human colorectal cancer cell line COLO205 that expressed BRAFV600E, respectively. In mutant BRAF melanoma cells, ERK1/2 activation can be effectively inhibited by PLX7904, but in mutant RAS-expressing cells, ERK1/2 is not overexpressed. In mutant BRAF melanoma cells, ERK1/2 activation can be effectively inhibited by PLX7940, but in mutant RAS-expressing cells, ERK1/2 is not overexpressed.
| Targets |
BRaf(V600E) (IC50 = 5 nM)
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| ln Vitro |
PLX7940 is able to efficiently inhibit activation of ERK1/2 in mutant BRAF melanoma cells but does not hyperactivate ERK1/2 in mutant RAS-expressing cells. In mutant N-RAS mediated vemurafenib-resistant cells, PLX7904 promotes apoptosis and inhibits entry into the S phase as well as anchorage-independent growth, which is consistent with ERK1/2 re-activation driving the re-acquisition of malignant properties. Additionally, PLX7904 is being tested in human SCC cell line A431 and human breast adenocarcinoma cell line SKBR3 because these cells activate the MAPK pathway by upstream signals feeding into RAS (through overexpression of the EGFR and HER2 receptors, respectively)[1][2].
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| ln Vivo |
PLX7904 inhibits the COLO205 xenograft growth in eight mice per group[1].
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| Enzyme Assay |
PLX7904 (also known as PB04) is a novel potent and selective paradox-breaker B-Raf inhibitor with IC50 of ~5 nM against BRAFV600E in mutant RAS expressing cells.
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| Cell Assay |
For MTT assays, 2×103 cells are seeded in triplicate in 96 wells of their regular culture medium (which contains PLX4720 for PRT lines). The medium is replaced the following day with the specified RAF inhibitor after cells have been washed twice with PBS. The medium is changed after 48 hours, and then after an additional 48 hours, 10 μL of the 5 mg/mL MTT reagent is added to the wells and incubated for three hours. Then, formazan crystals are solubilized over night with a 1:10 dilution of 0.1 M glycine (pH 10.5) in DMSO. Then, using a Multiskan® Spectrum spectrophotometer, wells are evaluated at 450 nM. The results shown are a composite of three separate experiments and have been normalized to DMSO conditions. The error bars that are displayed are an accurate representation of the standard error of the mean.
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| Animal Protocol |
Bovine insulin is added to DMEM with 10% FBS, 1% penicillin/streptomycin, and 1% bovine insulin during the culture of COLO205 tumor cells at 37°C. Female Balb/C nude mice, 6–8 weeks old, weighing about 18–22 g, are subcutaneously injected at the right flank with COLO205 tumor cells (5×106) in 0.1 mL of PBS mixed with matrigel (50:50) to test the development of tumors. Eight mice are randomly assigned to each treatment group so that the mean weight and tumor size are balanced when the mean tumor size reaches about 100 mm3. DMEM 10% FBS 1% penicillin/streptomycin is used to grow B9 cells. The cells are trypsinized, washed three times with 20 mL RPMI, and then re-suspended, counted, and volume-adjusted to a final concentration of 5×107 cells per milliliter before final centrifugation. In 6- to 7-week-old female nude Balb/c mice, 5×106 cells are subcutaneously injected to begin B9 xenografts. When the average tumor size reaches 50–70 mm3, compound dosing begins. To maintain a balance between the average tumor size and body weight, animals are evenly distributed among treatment groups (n=10). Animals are given vehicle, vemurafenib 50 mg per kg, or PLX7904 50 mg per kg twice daily for days 1 through 14 and once daily for days 15 through 28. In weeks three and four, 2 g of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 200 l of acetone is applied to the skin of every mouse.
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| References |
| Molecular Formula |
C24H22F2N6O3S
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| Molecular Weight |
512.53
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| Exact Mass |
512.14
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| Elemental Analysis |
C, 56.24; H, 4.33; F, 7.41; N, 16.40; O, 9.36; S, 6.26
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| CAS # |
1393465-84-3
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CCN(C)S(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=C2C=C(C=N3)C4=CN=C(N=C4)C5CC5)F
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| InChi Key |
DKNZQPXIIHLUHU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H22F2N6O3S/c1-3-32(2)36(34,35)31-19-7-6-18(25)20(21(19)26)22(33)17-12-30-24-16(17)8-14(9-29-24)15-10-27-23(28-11-15)13-4-5-13/h6-13,31H,3-5H2,1-2H3,(H,29,30)
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| Chemical Name |
5-(2-cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridine
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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 (4.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9511 mL | 9.7555 mL | 19.5111 mL | |
| 5 mM | 0.3902 mL | 1.9511 mL | 3.9022 mL | |
| 10 mM | 0.1951 mL | 0.9756 mL | 1.9511 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.
 Paradox breaker RAF inhibitors inhibit phosphorylation of ERK1/2 in mutant BRAF splice variant-expressing cells.Pigment Cell Melanoma Res.2014 May;27(3):479-84. |
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 Inhibition of G1/S cell cycle events in mutant BRAF splice variant-expressing cells treated with PB inhibitors.Pigment Cell Melanoma Res.2014 May;27(3):479-84. |
 Paradox breaker RAF inhibitors block growth of mutant BRAF splice variant-expressing cells.Pigment Cell Melanoma Res.2014 May;27(3):479-84. |
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