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Purity: ≥98%
PLX4720 (PLX-4720; PLX 4720), a 7-azaindole/pyrrolopyridine-based vemurafenib derivative discovered by a structure-guided discovery approach, is a novel, potent and selective inhibitor of B-RafV600E mutant with potential antitumor activity. In a cell-free assay, it inhibits B-RafV600E with an IC50 of 13 nM and is 10 times more selective for B-RafV600E than for wild-type B-Raf. Oral administration of PLX-4720 causes tumor growth delays in B-RafV600E-dependent tumor xenograft models, induces cell cycle arrest and apoptosis in B-RafV600E-positive melanoma cells, and inhibits ERK phosphorylation in tumor cell lines containing B-RafV600E.
| Targets |
B-Raf (V600E) (IC50 = 13 nM); B-Raf (IC50 = 160 nM); BRK (IC50 = 130 nM); ; FRK (IC50 = 1300 nM); Csk (IC50 = 1500 nM); Src (IC50 = 1700 nM); FAK (IC50 = 1700 nM); FGFR (IC50 = 1900 nM); KDR (IC50 = 2300 nM); HGK (IC50 = 2800 nM); CSF1R (IC50 = 3300 nM); Aurora A (IC50 = 3400 nM)
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| ln Vitro |
PLX-4720 exhibits >10 times selectivity against wild-type B-Raf and >100 times selectivity over other kinases, including Frk, Src, Fak, FGFR, and Aurora A, with an IC50 of 1.3-3.4 μM. PLX-4720 significantly reduces the ERK phosphorylation in cell lines expressing B-RafV600E, but not in cells expressing wild-type B-Raf (IC50 = 14–46 nM). PLX-4720 significantly slows the expansion of tumor cell lines that carry the B-RafV600E oncogene, including COLO205, A375, WM2664, and COLO829, with GI50 values of 0.31 μM, 0.50 μM, 1.5 μM, and 1.7 μM, respectively. Additionally, treatment with PLX-4720 at 1 μM only causes cell cycle arrest and apoptosis in B-RafV600E-positive 1205Lu cells while having no effect on B-Raf wild-type C8161 cells[1]. In comparison to PTEN-cell lines (4-fold), PLX-4720 treatment (10 μM) significantly increases the expression of BIM in PTEN+ cells by > 14 times, which provides an explanation for PTEN-cells' resistance to PLX-4720's ability to induce apoptosis[2].
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| ln Vivo |
In B-RafV600E-dependent COLO205 tumor xenografts, oral administration of PLX-4720 at 20 mg/kg/day results in significant tumor growth delays and regressions, with no overtly harmful side effects in mice, even at doses as high as 1 g/kg. While having no effect on the C8161 xenografts containing wild-type B-Raf, PLX-4720 at 100 mg/kg twice daily almost completely eradicates the 1205Lu xenografts bearing B-RafV600E. When PLX-4720 is applied to cells carrying the V600E mutation, the anti-tumor effects are correlated with the blockade of the MAPK pathway[1]. Treatment with PLX-4720 at 30 mg/kg/day significantly inhibits the growth of 8505c xenograft tumors by >90% and significantly lowers distant lung metastases[3].
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| Enzyme Assay |
In 20 mM Hepes (pH 7.0), 10 mM MgCl2, 1 mM DTT, 0.01% Tween-20, 100 nM biotin-MEK protein, varying ATP concentrations, and increasing concentrations of PLX-4720, 20-μL reactions are carried out for each enzyme (0.1 ng). At 2, 5, 8, 10, 20, and 30 minutes, reactions are stopped using 5 μL of a solution containing 20 mM hepes (pH 7.0), 200 mM sodium chloride, 80 mM EDTA, and 0.3% BSA. The AlphaScreen Protein A Detection Kit's phospho-MEK Antibody, Streptavidin-coated Donor beads, and Protein A Acceptor beads are also included in the stop solution. For 30 minutes, the antibody and beads are preincubated in stop solution at room temperature in the dark. The final antibody dilution is 1/2000, and the final bead concentration is 10 g/mL. The assay plates are read on a PerkinElmer AlphaQuest reader after an hour of room temperature incubation.
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| Cell Assay |
PLX-4720 is applied to cells at different concentrations for 24, 48, and 72 hours. The MTT assay or CellTiter-Glo Luminescent Cell Viability Assay are used to measure cell proliferation. Supernatant and cells are collected, pelleted, and fixed with 70% ethanol for cell cycle analysis. Cells are incubated for 1 hour at 37°C in 0.5 mg/mL RNase I to remove any remaining RNA contamination before staining with propidium iodide (10 μg/mL). Following that, samples are examined using the EPICS XL device. Media and cells are collected, pelleted, and stained with annexin-FITC and propidium iodide to determine the level of apoptosis. The EPICS XL instrument is then used to analyze the samples.
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| Animal Protocol |
SCID mice have their flanks injected subcutaneously with 2×106 metastatic melanoma cells, which are given approximately two weeks to reach a volume of 0.125 mm3. The animals then either receive 100 mg/kg PLX4720 (oral gavage) or vehicle control twice daily for 15 days. The tumor volume is measured every 72 hours. Normalized to the tumor volume on the first day of treatment, the average tumor size for each respective group. Animals are put to death 15 days into the treatment process, and tumors are removed, formalin-fixed, paraffin-embedded, and immunohistochemically examined.
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| References |
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| Molecular Formula |
C17H14CLF2N3O3S
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| Molecular Weight |
413.83
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| Exact Mass |
413.04
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| Elemental Analysis |
C, 49.34; H, 3.41; Cl, 8.57; F, 9.18; N, 10.15; O, 11.60; S, 7.75
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| CAS # |
918505-84-7
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| Related CAS # |
PLX-4720-d7;1304096-50-1
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| Appearance |
white solid powder
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| SMILES |
CCCS(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=C2C=C(C=N3)Cl)F
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| InChi Key |
YZDJQTHVDDOVHR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H14ClF2N3O3S/c1-2-5-27(25,26)23-13-4-3-12(19)14(15(13)20)16(24)11-8-22-17-10(11)6-9(18)7-21-17/h3-4,6-8,23H,2,5H2,1H3,(H,21,22)
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| Chemical Name |
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide
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| Synonyms |
PLX 4720; PLX4720; PLX-4720
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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 |
| 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) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4165 mL | 12.0823 mL | 24.1645 mL | |
| 5 mM | 0.4833 mL | 2.4165 mL | 4.8329 mL | |
| 10 mM | 0.2416 mL | 1.2082 mL | 2.4165 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.
Antimetastatic effects of PLX4720 require NK cells. Cancer Res; 74(24); 7298–308, 2014 |
PLX4720 requires perforin and CD226 for optimal antimetastatic activity. |
qPCR analysis showing that PLX4720 (3μM) alters the expression of XBP1s mRNA. |
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