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

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製品説明

  • Compare Raf Inhibitors
    Raf製品生物活性の比較
  • 研究分野
  • Combination Therapy
    併用療法
  • Vemurafenib (PLX4032, RG7204)のメカニズム

製品の説明

生物活性

製品説明 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。
ターゲット 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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
A375 MorpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXPhXmViOTByIN88US=> NF\obpg6PiCq NHu3WnFFVVOR NUewWFc1UUN3ME20O{BvVQ>? NELXbIsyQDR3OEC1Ny=>
ARO M{\EeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mn3TNVAxKM7:TR?= MYC5OkBp M2fJTmROW09? NVK4SmVzUUN3ME2yNFUhdk1? NGHT[JMyQDR3OEC1Ny=>
NPA NFuw[JFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MnHQNVAxKM7:TR?= MU[5OkBp NIL1boxFVVOR NYCyToFGUUN3ME2yOkBvVQ>? M4jDb|E5PDV6MEWz
TPCI MmfDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYH0U49iOTByIN88US=> MVG5OkBp MXXEUXNQ NF[5N3hKSzVyPUGwMlc4KM7:TR?= M4DPclE5PDV6MEWz
A375 NXLwNZNRSXCxcITvd4l{KEG|c3H5 NUnXWIlsOTBizszN M4PvOWROW09? MYHQdo9ud3SnczDhdI9xfG:2aXOg[IVifGh? NYTsfpBrOTh2NUiwOVM>
ARO MVPGeY5kfGmxbjDBd5NigQ>? MWGxNEDPxE1? M4\UN|czKGh? NF\CeYlFVVOR MYnJcoR2[2W|IITo[UBz\WW6cILld5Nqd25ib3[geIhmKE6LUzDweY1x M3zHeVE5PDV6MEWz
8505C (BRAF V600E/V600E) NHf5WmJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXu5OkBp Ml\nTWM2OD13NzDuUUA> NIfjdnkzODF2OUGzOi=>
SW1736 (BRAF WT/V600E) MnW1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{\MPVk3KGh? MnXpTWM2OD1{OTDuUS=> MUOyNFE1QTF|Nh?=
BHT101 (BRAF WT/V600E) MkTGS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml;ZPVYhcA>? MW\JR|UxRTl5IH7N M1ywd|IxOTR7MUO2
BCPAP (BRAF WT/V600E) NVjjVWt{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIDIc206PiCq NYHzdHlyUUN3ME23PEBvVQ>? NFP5UYUzODF2OUGzOi=>
C643 (HRAS G13R)≥ 500 NUnQOoNMT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnmzPVYhcA>? NEfab4NKSzVyIPMJqUA2ODBibl2= MXeyNFE1QTF|Nh?=
HTH7 (NRAS Q61R) NEH3VGdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoTzPVYhcA>? MonFTWM2OOLLpTCxNFAxKG6P NX7DfFUyOjBzNEmxN|Y>
CAL62 (KRAS G12R) > 1000 > 1000 M1TGdGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmPTPVYhcA>? MnH0TWM2OD5iMUCwNEBvVQ>? MVSyNFE1QTF|Nh?=
TPC-1 (RET/PTC1) MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4LUflk3KGh? M133fmlEPTEkibWxNFAxKG6P MmjFNlAyPDlzM{[=
PC MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYq5OkBp NEPtUmVKSzVyPjCxNFAxKG6P MVOyNFE1QTF|Nh?=
Calu-6 M2r6OGZ2dmO2aX;uJGF{e2G7 NXnlT|dOOeLCid88US=> MYKxJIg> MmW2SG1UVw>? NYjUNZhkSWO2aY\heIV{KE2HSz;FVmshcW5iY3XscJMhf2m2aDD3bYxlNXS7cHWgRnJCTg>? NYTCS3NpOjBzN{m3NFU>
C4 MWXGeY5kfGmxbjDBd5NigQ>? M4PwU|Mh|ryP Mli5OFghcA>? MmLjSG1UVw>? NFTDdXhKdmO{ZXHz[ZMh[2:ubHHn[Y4he3mwdHjld4l{KGGwZDDk[YNz\WG|ZYOgTWwuQCCneIDy[ZN{cW:w MmrwNlU6QDl3ME[=
VMM12 NHXP[4ZHfW6ldHnvckBCe3OjeR?= NE\I[3Q{KM7:TR?= MoTYOFghcA>? MmPlSG1UVw>? MYHJcoNz\WG|ZYOgZ49tdGGpZX6gd5lvfGinc3nzJIFv\CCmZXPy[YF{\XNiSVytPUBmgHC{ZYPzbY9v NITsbFkzPTl6OUWwOi=>
SKMEL19 NV3SS|BtTnWwY4Tpc44hSXO|YYm= NH\Ie3M3KM7:TR?= M{j0TFQ5KGh? M2Lu[2ROW09? M2TMPXRzcWepZYLzJGVTKHO2cnXzdy=> MmL4NlM{PjJ{NEC=
UKF-NB-3 (ABCB1) NGnpTpJHfW6ldHnvckBCe3OjeR?= M4m2Z|EvOjViwsXN NYnSSnhvOiCq MVrEUXNQ M{jYO2VvcGGwY3XzJIFk[3WvdXzheIlwdiCxZjD0bIUh\my3b4Lld4NmdnRiQVLDRlEhe3Wkc4TyZZRmKHKqb3ThcYlv\SBzMkO= M3G2XlI1PzN3N{[2
UKF-NB-3 MoXQSpVv[3Srb36gRZN{[Xl? NXzWNFVYOS5{NTFCuW0> NXTNTXdxOiCq M{jHTGROW09? MlXtV4lodmmoaXPhcpRtgSCjZn\lZ5R{KG:wIHHjZ5VufWyjdHnvckBw\iC2aHWg[ox2d3Knc3PlcpQhSUKFQkGgd5Vje3S{YYTlJJJpd2SjbXnu[UAyOjN? NYnxSms2OjR5M{W3OlY>
A375 (BRAFV600E) M2\hO2Z2dmO2aX;uJGF{e2G7 NWTVRnpbQCCq NHPocotFVVOR MXjJcoNz\WG|ZYOgbY51emGlZXzseYxieiCUT2OgZY5lKE6RIHzleoVteyB? NGK1XHUzPTN4M{[0OC=>

... Click to View More Cell Line Experimental Data

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.

プロトコル (参考用のみ)

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]

細胞株 MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058 cells
濃度 0–10 μM , dissolved in DMSO
反応時間 5 days
実験の流れ 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
投与方法 Oral gavage twice daily

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Vemurafenib (PLX4032, RG7204) SDF
分子量 489.92
化学式

C23H18ClF2N3O3S

CAS No. 918504-65-1
保管 3年-20℃
2年-80℃in solvent
別名 RO5185426
溶解度 (25°C) * In vitro DMSO 97 mg/mL (197.99 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 4% DMSO+30% PEG 300+5% Tween 80+ddH2O 5mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 N-​[3-​[[5-​(4-​chlorophenyl)​-​1H-​pyrrolo[2,​3-​b]​pyridin-​3-​yl]​carbonyl]​-​2,​4-​difluorophenyl]​-1-​propanesulfonamide

文献中の引用 (67)

Frequently Asked Questions

  • Question 1
    How about the half-life of Vemurafenib(S1267)?

    Answer: It was reported that the half-life of the compound is 57 hours.

  • Question 2
    The vemurafenib power, when prepared in 4% DMSO/30% PEG 300/5% Tween 80/ddH2O solutions, form a pellet down the tube?

    Answer: When prepare this kind of vehicle, please dissolve the drug in DMSO clearly first. If it dissolves not readily, please sonicate and warm in the water bath at about 45 degree. Then add PEG and Tween. After they mixed homogeneously, then dilute with water.

技術サポート&よくある質問(FAQ)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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