BGJ398 (NVP-BGJ398)

BGJ398 (NVP-BGJ398)は、強力で選択的な線維芽細胞成長因子レセプター家族阻害剤で、FGFR1, FGFR2, FGFR3 と FGFR4に作用すると、 IC50がそれぞれ0.9 nM、 1.4 nM、 1 nM と60 nMになる。

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BGJ398 (NVP-BGJ398) 化学構造
分子量: 560.48

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製品説明

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製品の説明

生物活性

製品説明 BGJ398 (NVP-BGJ398)は、強力で選択的な線維芽細胞成長因子レセプター家族阻害剤で、FGFR1, FGFR2, FGFR3 と FGFR4に作用すると、 IC50がそれぞれ0.9 nM、 1.4 nM、 1 nM と60 nMになる。
ターゲット FGFR1 FGFR2 FGFR3 FGFR4
IC50 0.9 nM 1.4 nM 1 nM 60 nM [1]
In vitro試験 BGJ398 also prevents VEGFR2 with low potency. The IC50 of BGJ398 for inhibiting VEGFR2 is 0.18 μM. BGJ398 suppresses other kinases including ABL, FYN, KIT, LCK, LYN and YES with IC50 of 2.3 μM, 1.9 μM, 0.75 μM, 2.5 μM, 0.3 μM and 1.1 μM, respectively. At the cellular level, BGJ398 inhibits the proliferation of the FGFR1-, FGFR2-Q, and FGFR3-dependent BaF3 cells with IC50 of 2.9 μM, 2.0 μM and 2 μM, respectively. BGJ398 interferes with autophosphorylation on specific tyrosine residues including FGFR-WT, FGFR2-WT, FGFR3-K650E, FGFR3-S249C and FGFR4-WT with IC50 of 4.6 nM, 4.9 nM, 5 nM, 5 nM and 168 nM, respectively. BGJ398 suppresses proliferation of the cancer cells with wild-type (WT) FGFR3 overexpression such as RT112, RT4, SW780 and JMSU1 with IC50 of 5 nM, 30 nM, 32 nM and 15 nM, respectively. [1]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
HCC M17vb2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlnxNU0zPTByIH7N NIrJco01QCCq NHzOfGnDqEmFNUC9JFI{PTokgJnucS=> M{TTSlI2Pjh6N{Sz
HCC MmHLS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIfsWVgyNTJ3MECgcm0> MkfSOFghcA>? NFrFcpdKSzVyPUGxNlTjiImwbR?= Mo\LNlU3QDh5NEO=
HCT116 MVfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV7wV3ZnPDhiaB?= NGPTfnhKSzVyPUOg{txO NYHWRlUxOjR3MEO1N|g>
HKH2 NWnDV|JvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NITzXWI1QCCq NVrtR3dIUUN3ME20JO69VQ>? NHG5[YgzPDVyM{WzPC=>
RKO MoL2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NX3Vco1TPDhiaB?= MWnJR|UxRTFwMjFOwG0> NXvnZZZ3OjR3MEO1N|g>
LS174T NWrBOmVbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnzXOFghcA>? MV\JR|UxRTRizszN Mlu5NlQ2ODN3M{i=
HCD9 NXP5epF4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmXLNE42NTVizszN MVe0PE84OiCq Mm\iSG1UVw>? Mlna[IVkemWjc3XzJINmdGxidnnhZoltcXS7 M{\mO|I1OTN3OEG2
HCT116 NFm4UHBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlzGNE42NTVizszN M2mwcFQ5Nzd{IHi= MmLoSG1UVw>? NWPucYl[\GWlcnXhd4V{KGOnbHygeoli[mmuaYT5 MoPkNlQyOzV6MU[=
SNU-C1 NX\qfI9XT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFnTTGIxNjVvNTFOwG0> NYf5SnFDPDhxN{KgbC=> MWjEUXNQ Mkjaco8h\W[oZXP0 NIfKS48zPDF|NUixOi=>
MFE280 NFzRdWJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVfSR3JEUUN3ME2yMlY{KMLzIECuPFIh|ryP NEDmcZkzOzR2M{iwOS=>
AN3CA MoSyS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2f5VWlEPTB;MT6wNEDDuSByLkKwJO69VQ>? M2m5c|I{PDR|OEC1
HEC155 MmDPS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MU\JR|UxRTRwN{SgxtEhOS5yOTFOwG0> NH7lR|QzOzR2M{iwOS=>
MFE296 M{PKOGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHfVPJBKSzVyPUKuPFYhyrFiMD6yNEDPxE1? NIGzUnYzOzR2M{iwOS=>
SPAC1S NELqRWtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHzOU|lKSzVyPUOuNVkhyrFiMD65N{DPxE1? M{nYUVI{PDR|OEC1
RL952 MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{jyT2lEPTB;Mz60NUDDuSByLkKzJO69VQ>? NX7GfnFVOjN2NEO4NFU>
EN1 NFHwOY1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M365NWlEPTB;ND63OUDDuSByLk[yJO69VQ>? NYXWUIdEOjN2NEO4NFU>
SNGII M3zRR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mn3KTWM2OD12LkK5JOKyKDBwNUig{txO NXfpXGNbOjN2NEO4NFU>
ISHIKAWA M4TsVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmLDTWM2OD13LkS4JOKyKDBwMEOg{txO M4P0XFI{PDR|OEC1
HEC1A NXzMTmwzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVPJR|UxRTFyLkCwJOKyKDFwMECg{txO NG\OSZIzOzR2M{iwOS=>
KLE MUnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4LTNGlEPTB;Mz6wN{DDuSByLkGxJO69VQ>? MU[yN|Q1OzhyNR?=
SNGM NFX2NGpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Mn7OTWM2OD13LkCwJOKyKDBwNEGg{txO MWiyN|Q1OzhyNR?=
USPC2 MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXTt[ok5UUN3ME23MlAxKMLzIECuNlEh|ryP NF\4fGUzOzR2M{iwOS=>
EN M{PNRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUnJR|UxRTZwMEOgxtEhOC5|MTFOwG0> MViyN|Q1OzhyNR?=
MFE319 M{[0Z2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHPafoxKSzVyPUWuN|chyrFiMD6wN{DPxE1? Mmr6NlM1PDN6MEW=
EFE184 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NF20So9KSzVyPUiuNFQhyrFiMD62PUDPxE1? MXGyN|Q1OzhyNR?=
ECC1 NVPtc3lqT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWnJR|UxRTZwN{SgxtEhOC53OTFOwG0> MnGyNlM1PDN6MEW=
HEC1B M{nBRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NV7aO4pxUUN3ME22MlQ2KMLzIECuOlch|ryP MXiyN|Q1OzhyNR?=
USPC1 NEjKW5hIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHrUT|hKSzVyPUWuO|UhyrFiMD61NEDPxE1? NYTZRmZ7OjN2NEO4NFU>
SPAC1L MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NYC2UWRSUUN3ME20MlkzKMLzIECuOVAh|ryP MlfTNlM1PDN6MEW=

... Click to View More Cell Line Experimental Data

In vivo試験 In this orthotopic xenograft bladder cancer model, BGJ398 induces tumor growth inhibition and stasis after oral administration for 12 consecutive days at the doses of 10 and 30 mg/kg, respectively. Interestingly, the animals that received BGJ398 exhibits either no body weight loss (10 mg/kg) or 10% body weight gain (30 mg/kg), a further indication of efficacy. RT112 tumor-bearing and female Rowett rats receive a single oral administration of the monophosphate salt of BGJ398 at the doses of 4.25 and 8.51 mg/kg. BGJ398 significantly decreases the levels of pFRS2 and pMAPK in a dose-dependent manner. BGJ398 inhibits significantly bFGF-stimulated angiogenesis in a dose-dependent manner. However, BGJ398 does not impair VEGF-induced blood vessel formation. [1]
臨床試験 BGJ398 is currently in a Phase I clinical trial in the treatment of the renal tumors.
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Radiometric kinase assay The enzymatic kinase activity is assessed by measuring the phosphorylation of a synthetic substrate by the purified GST-fusion FGFR3-K650E kinase domain, in the presence of radiolabeled ATP. Enzyme activities are measured by mixing 10 μL of a 3-fold concentrated BGJ398 solution or control with 10 μL of the corresponding substrate mixture (peptidic substrate, ATP and [γ33P]ATP). The reactions are initiated by addition of 10 μL of a 3-fold concentrated solution of the enzyme in assay buffer. The final concentrations of the assay components are as following: 10 ng of GST-FGFR3-K650E, 20 mM Tris-HCl, pH 7.5, 3 mM MnCl2, 3 mM MgCl2, 1 mM DTT, 250 μg/mL PEG 20000, 2 μg/mL poly(EY) 4:1, 1% DMSO and 0.5 μM ATP (γ-[33P]-ATP 0.1 μCi). The assay is carried out according to the filter binding (FB) method in 96-well plates at room temperature for 10 minutes in a final volume of 30 μL including BGJ398. The enzymatic reactions are stopped by the addition of 20 μL of 125 mM EDTA, and the incorporation of 33P into the polypeptidic substrates is quantified as following: 30 μL of the stopped reaction mixture are transferred onto Immobilon-PVDF membranes previously soaked for 5 minutes with methanol, rinsed with water, soaked for 5 min with 0.5% H3PO4, and mounted on vacuum manifold with disconnected vacuum source. After spotting, vacuum is connected, and each well rinsed with 0.5% H3PO4 (200 μL). Free membranes are removed and ished four times on a shaker with 1% H3PO4 and once with ethanol. Membranes are dried and overlaid with addition of 10 μL/well of a scintillation fluid. The plates are eventually sealed and counted in a microplate scintillation counter. IC50 values are calculated by linear regression analysis of the percentage inhibition of the BGJ398.

細胞アッセイ: [1]

細胞株 Murine BaF3 cell lines
濃度 0 μM-0.1 μM
反応時間 48 hours
実験の流れ Murine BaF3 cell lines, whose proliferation and survival has been rendered IL-3-independent by stable transduction with tyrosine kinases activated either by mutation or fusion with a dimerizing partner, are cultured in RPMI-1640 media supplemented with 10% FBS, 4.5 g/L glucose, 1.5 g/L sodium bicarbonate, and Pen/Strep. Cells are passaged twice weekly. BGJ398-mediated inhibition of BaF3 cell proliferation and viability is assessed using a Luciferase bioluminescent assay. Exponentially growing BaF3 or BaF3 Tel-TK cells are seeded into 384-well plates (4250 cells/well) at 50 μL/well using a μFill liquid dispenser in fresh medium. BGJ398 is serially diluted in DMSO and arrayed in a polypropylene 384-well plate. Then 50 nL of BGJ398 are transferred into the plates containing the cells by using the pintool transfer device, and the plates incubated at 37 °C (5% CO2) for 48 hours. Then 25 μL of Bright-Glo are added, and luminescence is quantified using an Analyst-GT. Custom curve-fitting software is used to produce a logistic fit of percent cell viability as a function of the logarithm of inhibitor concentration. The IC50 value is determined as the concentration of BGJ398 needed to reduce cell viability to 50% of a DMSO control.

動物実験: [1]

動物モデル Athymic nude-nu mice bearing parental RT112 cell line
製剤 PEG300/D5W (2:1, v/v)
投薬量 10 mg/kg/qd and 30 mg/kg/qd
投与方法 Oral administration

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 BGJ398 (NVP-BGJ398) SDF
分子量 560.48
化学式

C26H31Cl2N7O3

CAS No. 872511-34-7
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 1 mg/mL warming (1.78 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/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 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)-1-methylurea

カスタマーフィードバック (3)


Click to enlarge
Rating
Source Hepatology, 2014, 59(4), 1427-34. BGJ398 (NVP-BGJ398) purchased from Selleck
Method Western blot
Cell Lines NIN3T3 cells
Concentrations 0.2, 1 uM
Incubation Time 2 h
Results BGJ398 significantly inhibited the phosphorylation of MAPK.

Click to enlarge
Rating
Source Hepatology, 2014, 59(4), 1427-34. BGJ398 (NVP-BGJ398) purchased from Selleck
Method colony formation assay
Cell Lines NIN3T3 cells
Concentrations 0.2 uM
Incubation Time 2 h
Results BGJ398 reduced in vitro anchorage-independent colony formation to the level observed in KD mutant expressing cells.

Click to enlarge
Rating
Source J Cell Physiol, 2014, 229(11), 1647-59. BGJ398 (NVP-BGJ398) purchased from Selleck
Method Western blot
Cell Lines HERS cells
Concentrations 0.2 uM
Incubation Time 48 h
Results BGJ39 not only reversed the down-expression of E-cadherin, but also weakened the expression of BSP and OPN. BGJ398 down-regulated the cementoblast-like induction of FGF2 by reducing the expression of BSP and OPN compared with HERS cells treated with FGF2.

文献中の引用 (15)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID