Vemurafenib (PLX4032, RG7204)

Vemurafenib (PLX4032, RG7204)新しくて強力な阻害剤で、 B-RAFV600Eに作用すると、IC50 が 31 nMになる。

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Vemurafenib (PLX4032, RG7204) 化学構造
分子量: 489.92



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情報 Vemurafenib (PLX4032, RG7204)新しくて強力な阻害剤で、 B-RAFV600Eに作用すると、IC50 が 31 nMになる。
目標 B-RafV600E C-Raf MAP4K5 (KHS1) SRMS ACK1 FGR
IC50 31 nM 48 nM 51 nM 18 nM 19 nM 63 nM [1]
In vitro試験 PLX4032 inhibits B-RAFV600E, C-RAF, as well as wildtype B-RAF, with IC50 of 31 nM, 48 nM and 100 nM, respectively. PLX4032 also inhibits several non-RAF kinases, including ACK1, KHS1, and SRMS, with IC50 of 18 nM to 51 nM. [1] In melanoma cell lines, the inhibitory effect by PLX4032 depends on B-RAF mutational status, because PLX4032 potently inhibits those harboring B-RAF V600 mutants, including V600E, V600D, V600K, and V600R, but not wildtype or other mutants. The IC50 values of PLX4032 on these cells, including MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058, ranges from 20 nM to 1 μM. In these cells, PLX4032 (0.1 μM to 30 μM) also inhibits the phosphorylation of both MEK1/2 and ERK1/2. [2] PLX4032 is highly effective in the treatment of melanoma, for its ability of inhibiting B-RAFV600E. However, PLX4032 displays limited effect in colon cancer patients that also carrying B-RAFV600E oncoprotein. The reason for this is that, in colon cancer cells, B-RAFV600E inhibition by PLX4032 results in a rapid feedback EGFR activation, which compensates for the PLX4032-inhibited cell proliferation. [3]
In vivo試験 In B-RAFV600E-mutant mice xenograft models, PLX4032 (6 mg/kg–20 mg/kg) inhibits tumor growth. [1] In mice xenograft models of LOX, Colo829, and A375 cells, PLX4032 (12.5 mg/kg–100 mg/kg) inhibits tumor growth and prolongs mice survival. [2]
臨床試験 PLX4032 has recently been approved by US Food and Drug Administration (FDA) for the treatment of advanced metastatic melanoma with a B-RAFV600E mutation.
特集 A novel and potent inhibitor of the B-RAFV600E oncoprotein.

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

RAF kinase activity measurements The kinase activities of wild-type RAF and mutants are determined by measuring phosphorylation of biotinylated-BAD protein. For each enzyme (0.01 ng), 20 μL reactions are carried out in 20 mM Hepes (pH 7.0), 10 mM MgCl2, 1 mM DTT, 0.01% (v/v) Tween-20, 50 nM biotin-BAD protein, and 1 mM ATP at room temperature. Reactions are stopped at 5 min with 5 μL of a solution containing 20 mM Hepes (pH 7.0), 200 mM NaCl, 80 mM EDTA, 0.3% (w/v) bovine serum albumin (BSA). The stop solution also includes phospho-BAD (Ser112) antibody, streptavidin-coated donor beads, and protein A acceptor beads. The antibody and beads are pre-incubated in stop solution in the dark at room temperature for 30 min. The final dilution of antibody is 1/2000 and the final concentration of each bead is 10 μg/mL. The assay plates are incubated at room temperature for one hour and then are read on a PerkinElmer AlphaQuest reader. Mutant activities are the average of two different batches of purified protein assayed in duplicate in three different experiments.

細胞アッセイ: [2]

細胞系 MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058 cells
濃度 0–10 μM , dissolved in DMSO
処理時間 5 days
方法 Cellular proliferation is evaluated by MTT assay. Briefly, cells are plated in 96-well microtiter plates at a density of 1000 to 5000 cells per well in a volume of 180 μL. PLX4032 is prepared at 10 times the final assay concentration in media containing 1% DMSO. Twenty-four hours after cell plating, 20 μL of the appropriate dilution of PLX4032 are added to plates in duplicate. The plates are assayed for proliferation 6 days after the cells are plated. Percent inhibition is calculated and the IC50 is determined from the regression of a plot of the logarithm of the concentration versus percent inhibition.

動物実験: [2]

動物モデル Mice (athymic nude) xenograft models of LOX, Colo829, and A375 cells
製剤 Formulated as microprecipitated bulk powder (MBP), suspended at the desired concentration in an aqueous vehicle containing 2% Klucel LF, and adjusted to pH 4 with dilute HCl
投薬量 12.5 mg/kg–100 mg/kg
管理 Oral gavage twice daily



Download Vemurafenib (PLX4032, RG7204) SDF
分子量 489.92


CAS No. 918504-65-1
別名 RG7204
溶解度 (25°C)
  • DMSO 98 mg/mL
  • 水 <1 mg/mL
  • エタノール <1 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO


カスタマーレビュー (7)

Click to enlarge
Source J Invest Dermatol, 2013, ahead of print. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Western blot
Cell Lines A375 melanoma cells
Concentrations 0-10 μM
Incubation Time 6 h
Results The activation of Stat3 and the protein expression of PAX3 were both repressed in vemurafenib-sensitive (parental) A375 and UACC62 melanoma cells, but higher vemurafenib concentration were required in resistant A375 and UACC62 melanoma cells. Specifically, vemurafenib at 1 μM inhibited the expression of phospho-Stat3 in sensitive cells, but not in resistant cells. These results suggest that inhibition of Stat3 signaling represents a potential therapeutic strategy to overcome the acquired resistance to vemurafenib in melanoma cells.

Click to enlarge
Source Oncoimmunology, 2012, 1(9), 1476-1483. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method flow cytometry
Cell Lines tumor-infiltrating lymphocytes
Concentrations 100-250 nM
Incubation Time 72 h
Results Treatment with Vem significantly increased the frequency of TILs recognizing autologous melanoma cells and responding to them by producing Type 1 helper cytokines (Fig. A ) or by mobilizing cytotoxic granules (Fig. B ), confirming the polyfunctionality of newly-induced responses.

Click to enlarge
Source J Invest Dermatol, 2011, 131(10), 2087-95.. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Clonogenic assays
Cell Lines VM21/VM1 (c) cells
Concentrations 0.1 μM
Incubation Time 14 d
Results Combination of PD166866 with the V600E BRAF-specific inhibitor RG7204 (PLX4032) potently reduced clonogenic growth of VM21 and VM1 cells.

Click to enlarge
Source Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Western blot analysis/ In vitro colony formation assay
Cell Lines LOX IMVI melanoma cells
Concentrations 0-1 μM
Incubation Time 24 h
Results We therefore a ssessed the effe ct of the anti-E rbB3 anti-body A4 generated in our lab and able to inhibit the ligand-induced signaling and to potently induce receptor internalization and degradation, on vemurafenib-induced pErbB3 and pAKT levels and found that this was able to completely abrogate receptor phosphory l-ation and AKT signaling in all cell line s tested (Figure a)treatment with anti-ErbB3 mAb strongly potentiated growth inhibition by vemurafenib (Figure b and c). As expected only A3 but not A2 was able to completely abrogate vemurafenib-induced ErbB3 phosphorylation and AKT signaling (Figure d). Moreover in in vitro colony formation a ssays only A3 but not A2 strongly potentiated growth inhibition by vemurafenib(Figure e).

Click to enlarge
Source Dr Zhe-Sheng Chen of St. John's University. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Cell cytotoxicity assay
Cell Lines HEK293 cells, HEK293/MRP7 cells
Concentrations 20 μM
Incubation Time

Click to enlarge
Source Dr Zhe-Sheng Chen of St. John's University. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Cell cytotoxicity assay
Cell Lines H460 cells, H460/MX20 cells
Concentrations 20 μM
Incubation Time

Click to enlarge
Source Dr Zhe-Sheng Chen of St. John's University. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method [3H]-Mitoxantrone accumulation analysis
Cell Lines H460 cells, H460/MX20 cells
Concentrations 20 μM
Incubation Time 96 h
Results Vemurafenib increased the intra-cellular accumulation of Mitoxantrone in ABCG2 overexpressing H460/MX20 cells compared with parental H460 cells.

製品表彰状 (23)

  • Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. [Prahallad A, et al. Nature 2012;483(7387):100-3]

    PubMed: 22281684
  • MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. [Huang S, et al. Cell 2012;151(5):937-50]

    PubMed: 23178117
  • MDM4 is a key therapeutic target in cutaneous melanoma. [Gembarska A, et al. Nat Med 2012;18(8):1239-47]

    PubMed: 22820643
  • Preexisting MEK1 Exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors. [Shi H, et al. Cancer Discov 2012;2(5):414-24]

    PubMed: 22588879
  • A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. [Whittaker SR, et al. Cancer Discov 2013;3(3):350-62]

    PubMed: 23288408
  • Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. [Ohashi K, et al. Proc Natl Acad Sci U S A 2012;109(31):E2127-33]

    PubMed: 22773810
  • Characteristics of lung cancers harboring NRAS mutations. [Ohashi K, et al. Clin Cancer Res 2013;19(9):2584-91]

    PubMed: 23515407
  • Thyroid cancer cell resistance to gefitinib depends on the constitutive oncogenic activation of the ERK pathway [Frasca F,et al. J Clin Endocrinol Metab 2013;98(6):2502-12]

    PubMed: 23559083
  • Oncogenic B-RAF(V600E) Signaling Induces the T-Box3 Transcriptional Repressor to Repress E-Cadherin and Enhance Melanoma Cell Invasion. [Boyd SC, et al. J Invest Dermatol 2012;133(5):1269-77]

    PubMed: 23190890
  • Fibroblast growth factor receptors as therapeutic targets in human melanoma: synergism with BRAF inhibition. [Metzner T, et al. J Invest Dermatol 2011;131(10):2087-95]

    PubMed: 21753785
  • Stat3-Targeted Therapies Overcome the Acquired Resistance to Vemurafenib in Melanomas [Liu F, et al. J Invest Dermatol 2013;133(8):2041-9]

    PubMed: 23344460
  • Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. [Wagenaar TR, et al. Pigment Cell Melanoma Res 2013;27(1):124-33]

    PubMed: 24112705
  • Colloidal Aggregation Affects the Efficacy of Anticancer Drugs in Cell Culture. [Owen SC, et al. ACS Chem Biol 2012;7(8):1429-35]

    PubMed: 22625864
  • Aurora B is regulated by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway and is a valuable potential target in melanoma cells. [Bonet C, et al. J Biol Chem 2012;287(35):29887-98]

    PubMed: 22767597
  • Melanoma Chemotherapy Leads to the Selection of ABCB5-Expressing Cells. [Chartrain M, et al. PLoS One 2012;7(5):e36762]

    PubMed: 22675422
  • Functional profiling of live melanoma samples using a novel automated platform. [Schayowitz A, et al. PLoS One 2012;7(12):e52760]

    PubMed: 23285177
  • Anti-Cancer Drugs Elicit Re-Expression of UDP-Glucuronosyltransferases in Melanoma Cells. [Dellinger RW, et al. PLoS One 2012;7(10):e47696]

    PubMed: 23110092
  • High iodine blocks a Notch/miR-19 loop activated by the BRAFV600E oncoprotein and restores the response to TGFβ in thyroid follicular cells. [Fuziwara CS, et al. Thyroid 2013;10.1089/thy.2013.0398]

    PubMed: 23998804
  • Activation of an early feedback survival loop involving phospho-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies. [Fattore L, et al. J Transl Med 2013;11:180]

    PubMed: 23890105
  • Specifically targeting ERK1 or ERK2 kills Melanoma cells. [Qin J, et al. J Transl Med 2012;10:15]

    PubMed: 22277029
  • The proteasome inhibitor bortezomib inhibits the growth of canine malignant melanoma cells in vitro and in vivo. [Keita Ito, et al. The Veterinary Journal 2013;198(3):577-82]

    PubMed: 24035468
  • Phenotypic Profiling of Raf Inhibitors and Mitochondrial Toxicity in 3D Tissue Using Biodynamic Imaging. [An R ,et al. J Biomol Screen 2013;10.1177/1087057113516674]

    PubMed: 24361645
  • BRAF inhibition improves tumor recognition by the immune system: Potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer. [Donia M, et al. Oncoimmunology 2012;1(9):1476-1483]

    PubMed: 23264894



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