BMS-777607 化学構造
分子量: 512.89

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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 BMS777607は分子が小さいMet関連キナーゼ阻害剤、c-Met, Axl, Ron 、Tyro3に作用する時、IC50がそれぞれ3.9nM、1.1nM、1.8nMと4.3nMになる。
ターゲット c-Met Axl Ron Tyro3
IC50 3.9 nM 1.1 nM 1.8 nM 4.3 nM [1]
In vitro試験 BMS-777607 is a selective ATP-competitive Met kinase inhibitor which potently blocks the autophosphorylation of c-Met with IC50 of 20 nM in GTL-16 cell lysates, and demonstrates selective inhibition of proliferation in Met-driven tumor cell lines, such as GTL-16 cell line, H1993 and U87. [1] BMS-777607 inhibits hepatocyte growth factor (HGF)-triggered c-Met autophosphorylation with IC50 of <1 nM in PC-3 and DU145 prostate cancer cells. BMS 777607 has little effect on tumor cell growth, but exhibits inhibitory effect on HGF-induced cell scattering in PC-3 and DU145 cells, with almost complete inhibition at 0.5 μM. BMS 777607 also suppresses stimulated cell migration and invasion in a dose-dependent fashion (IC50 < 0.1 μM) in both cell lines. [2] Application of BMS 777607 (~10 μM) to the highly metastatic murine KHT cells for 2 hours potently eliminates basal levels of autophosphorylated c-Met with IC50 of 10 nM without affecting the total c-Met, leading to dose-dependent inhibition of phosphorylation of downstream signaling molecules including ERK, Akt, p70S6K and S6. Treatment with BMS-777607 (~1 μM) for 24 hours potently inhibits the KHT cell scatter, motility and invasion at doses in the nanomolar range which consists with MET gene knockdown, and modestly affects cell proliferation and colony formation. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
GTL-16 MmryT4lv[XOnIHHzd4F6 NFzSN2dFVVOR M2jlcIlvcGmkaYTzJG1mfCCtaX7hd4Uhf2m2aDDJR|UxKG:oIEGwNEBvVQ>? M{PHeVE6OjZyN{Gx
H1993 MX\Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MXf+NVAh|ryP NEXKOHRFVVOR NXu3epBmUUN3ME2xOVAhdk1? MXexPVI3ODdzMR?=
U87 NGTWWFlIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MlP0glExKM7:TR?= MnjySG1UVw>? MmmxTWM2OD1zNkCgcm0> NF\JbIgyQTJ4MEexNS=>
PC-3 NEm0cWJHfW6ldHnvckBie3OjeR?= MYiwMlEh|ryP MUfEUXNQ MWPlfIhq[mm2czDpcohq[mm2b4L5JIVn\mWldDDvckBJT0ZvaX7keYNm\CClZXzsJJNk[XS2ZYLpcoc> NV20Zm46OjB3MUW5OFM>
DU145 NFXKUVBHfW6ldHnvckBie3OjeR?= MkPrNE4yKM7:TR?= NXjRW3NmTE2VTx?= MV\lfIhq[mm2czDpcohq[mm2b4L5JIVn\mWldDDvckBJT0ZvaX7keYNm\CClZXzsJJNk[XS2ZYLpcoc> MoHQNlA2OTV7NEO=
PC-3 NHzlNHVHfW6ldHnvckBie3OjeR?= MXmwMlAyKM7:TR?= M{j6VmROW09? M3nH[ZN2eHC{ZYPz[ZMhUEeILXnu[JVk\WRiY3XscEBucWe{YYTpc44> M4DpVFIxPTF3OUSz
DU145 MUHGeY5kfGmxbjDhd5NigQ>? NWi0OGZDOC5yMTFOwG0> NYrpcoZXTE2VTx?= M1TwWpN2eHC{ZYPz[ZMhUEeILXnu[JVk\WRiY3XscEBucWe{YYTpc44> NFPzd|YzODVzNUm0Ny=>
PC-3 NF70dI1HfW6ldHnvckBie3OjeR?= MUSwMlEh|ryP MV3EUXNQ MmDibY1x[Wm{czDIS2YudWWmaXH0[YQh[2WubDDpcpZie2mxbh?= NEXnfGozODVzNUm0Ny=>
DU145 M33DZ2Z2dmO2aX;uJIF{e2G7 MUWwMlEh|ryP M3vQWmROW09? NH6yTo5qdXCjaYLzJGhITi2vZXTpZZRm\CClZXzsJIlvfmG|aX;u MmXzNlA2OTV7NEO=
PC-3 M{LUTWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MoPFglExKM7:TR?= NXjVRYV{TE2VTx?= NU\LNlNwemWmdXPld{Bk\WyuIIDyc4xq\mW{YYTpc44> MVWyNFUyPTl2Mx?=
KHT M3rVW2tqdmG|ZTDhd5NigQ>? NU\FR3A2TE2VTx?= NHXaXXljdG:la4OgeIhmKGNvTXX0JJNq\26jbHnu[{Bx[XSqd3H5JJdqfGhiSVO1NEBw\iBzMDDuUS=> NIfUcFQzOjJ6NkWyNy=>
KHT NGXGUJRHfW6ldHnvckBie3OjeR?= NIH6Vph,OSEQvF2= MVzEUXNQ Mmq1dJJmfmWwdIOgd5BwdnSjbnXveZMhU0iWIHPlcIwhe2OjdITldolv\yC5aYToJGlEPTBib3[gNE4yNTBwNTFOwG0> M4GzcFIzOjh4NUKz
KHT Mlq3SpVv[3Srb36gZZN{[Xl? MUD+NE42KM7:TR?= M4DYXWROW09? MXzpcohq[mm2czDj[YxtKG2rZ4LheIlwdg>? NXK0VJd[OjJ{OE[1NlM>
KHT Ml3ESpVv[3Srb36gZZN{[Xl? MkfEglAvPSEQvF2= NG\6em5FVVOR M{DiPYlvcGmkaYTzJINmdGxiaX72ZZNqd25? NE\5SnAzOjJ6NkWyNy=>
KHT M2C2bGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M{DzXJ4yOCEQvF2= M{jGTWROW09? M{DJfIlvcGmkaYTzJGtJXCClZXzsJJBzd2yrZnXyZZRqd25? M4LDWFIzOjh4NUKz
T-47D MlHSS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NVjLeFlNhjVizszN MmrWSG1UVw>? NX7NN25xcW6qaXLpeJMh[2WubDDwdo9tcW[ncnH0bY9v MlvuNlM1Pjh3Mkm=
ZR-75-1 M1TrTGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M3ewdp42KM7:TR?= NEXiXXhFVVOR MYDpcohq[mm2czDj[YxtKHC{b3zp[oVz[XSrb36= MXSyN|Q3QDV{OR?=
T-47D MY\GeY5kfGmxbjDhd5NigQ>? M1LOR|ExKM7:TR?= NUHyOnMxTE2VTx?= M4TwTmlv\HWlZYOgdI9tgXCub3nkfUBjgSB6NjCl MWSyN|Q3QDV{OR?=
ZR-75-1 NI\kXIRHfW6ldHnvckBie3OjeR?= NG\XVG8yOCEQvF2= MmHCSG1UVw>? NUjqOINbUW6mdXPld{Bxd2y7cHzvbYR6KGK7IEi4KS=> Mm\UNlM1Pjh3Mkm=
T-47D NEXBTY5HfW6ldHnvckBie3OjeR?= Ml;ENVAh|ryP MojmSG1UVw>? NH\oPZBqdmirYnn0d{BCXVKNLVKg[pVv[3Srb36gZY5lKGmwZIXj[ZMhcXS|IIDyc5RmcW5iZHXndoFl[XSrb36= M2D6TlI{PDZ6NUK5
CHRF M1fuN2Z2dmO2aX;uJIF{e2G7 NYC1c4NNOTBizszN NFf1RoFFVVOR M4PTdolvcGmkaYTzJINmdGxiZHn2bZNqd25? M4HFeFI2OzB2OUCw
HPDE NXfmfVAxTnWwY4Tpc44h[XO|YYm= MW[xNEDPxE1? MY\EUXNQ NInkSZRjdG:la4OgZ49ve3SrdIX0bZZmKGGldHn2ZZRqd25iYX7kJIRm[3KnYYPl[EBCU1Ric3nncoFtcW6p MnPHNlY1Pzd|MUS=
U118MG NX\HVG52U2mwYYPlJIF{e2G7 M2\2cJ4{KM7:TR?= NYThVWM2TE2VTx?= M{GxUYJtd2OtczDBXGwheGixc4Doc5J6dGG2aX;u M4\C[FI3QDR6NUK0
SF126 MW\LbY5ie2ViYYPzZZk> NY\JT3lWhjNizszN M{ixSWROW09? M13qfYJtd2OtczDBXGwheGixc4Doc5J6dGG2aX;u M376PFI3QDR6NUK0
U118MG NWX3NHgyS3m2b4jpZ4l1gSCjc4PhfS=> MUWxNk42KM7:TR?= NH65UWZFVVOR MnS1[IVkemWjc3XzJIdtcW:vYTDj[YxtKH[rYXLpcIl1gQ>? M3rmfVI3QDR6NUK0
SF126 NWfEW2h4S3m2b4jpZ4l1gSCjc4PhfS=> MWCxNk42KM7:TR?= NFTrN3NFVVOR MUjk[YNz\WG|ZYOg[4xqd22jIHPlcIwhfmmjYnnsbZR6 NFuzSXUzPjh2OEWyOC=>
U118MG M3K0PWFxd3C2b4Ppd{Bie3OjeR?= MmO1NVIvPSEQvF2= M1nQS2ROW09? MWnpcoR2[2W|IHfsbY9u[SClZXzsJIFxd3C2b4Ppdy=> NVHqRoVSOjZ6NEi1NlQ>
SF126 Mn[0RZBweHSxc3nzJIF{e2G7 NH;IfZgyOi53IN88US=> NHzzRVFFVVOR NE\LSY1qdmS3Y3XzJIdtcW:vYTDj[YxtKGGyb4D0c5Nqew>? M2HkZ|I3QDR6NUK0
U118MG M2\mN2Z2dmO2aX;uJIF{e2G7 NVTXO5Z3OTJwNTFOwG0> NWT1PFJbTE2VTx?= MV7icI9kc3NiZ3zpc41iKGOnbHygcYloemG2aX;uJIFv\CCrbo\hd4l3\SCpcn;3eIgheGG2dHXyci=> NGTQVWszPjh2OEWyOC=>
SF126 MUPGeY5kfGmxbjDhd5NigQ>? MV2xNk42KM7:TR?= NYTTPW1qTE2VTx?= NE\ibmxjdG:la4Og[4xqd22jIHPlcIwhdWmpcnH0bY9vKGGwZDDpcpZie2m4ZTDndo94fGhicHH0eIVzdg>? NIqwRZAzPjh2OEWyOC=>

... Click to View More Cell Line Experimental Data

In vivo試験 Oral administration of BMS 777607 (6.25-50 mg/kg) significantly reduces tumor volumes of the GTL-16 human tumor xenografts in athymic mice with no observed toxicity. [1] Administration of BMS 777607 (25 mg/kg/day) decreases the number of KHT lung tumor nodules (28.3%), improves the morphological hemorrhage, and significantly impairs the metastatic phenotype in the 6-8 week-old female C3H/HeJ mice injected with rodent fibrosarcoma KHT cells without apparent systemic toxicity compared to the control treatment. A low dose of BMS 777607 (10 mg/kg) also offers a mild but not significant inhibition of lung nodule formation compared to the vehicle control. [3]
臨床試験 Phase I/II has been completed in the study to find the maximum tolerated dose and the preliminary activity of BMS-777607 in subjects with advanced or metastatic solid tumors, hormone refractory prostate cancer, head and neck squamous cell carcinoma, and t
特集 A potent inhibitor of the Met family, and >40-fold selectivity vs. Lck, VEGFR2, and TrkA/B and >500-fold selective vs. other receptor and non-receptor kinases.

プロトコル (参考用のみ)

キナーゼアッセイ: [4]

Met Kinase Assay The kinase reaction consists of baculovirus expressed GST-Met, 3 μg of poly(Glu/Tyr), 0.12 μCi 33P γ-ATP, 1 μM ATP in 30 μL of kinase buffer (20 mM Tris-Cl, 5 mM MnCl2, 0.1 mg/mL BSA, 0.5 mM DTT). Reactions are incubated for 1 hour at 30 °C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 8%. TCA precipitates are collected onto GF/C unifilter plates using a Filtermate universal harvester, and the filters are quantitated using a TopCount 96-well liquid scintillation counter. Dose response curves are generated to determine the concentration required to inhibit 50% of substrate phosphorylation (IC50). BMS 777607 is dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at 10 concentrations, in duplicate.

細胞アッセイ: [3]

細胞株 Rodent fibrosarcoma KHT cells
濃度 Dissolved in DMSO as a stock solution (10 mM), final concentration ~10 μM.
反応時間 2, 24 and 96 hours
実験の流れ KHT cells are exposed to serial dilution of BMS 777607 for 96 hours, then the MTT assay and trypan blue exclusion are used for the determination of cell proliferation and cell death, respectively. KHT cell colonies are incubated with BMS 777607 for 24 hours and then stained with crystal violet (0.1%) and photographed for the assessment of cell scattering. 2 mm scratch on the confluent KHT cell monolayer is made using a sterilized 1 ml pipette tip followed by treated with BMS-777607 for 24 hours, then the number of cells that have migrated into the denuded area is counted on 4 random fields for the evaluation of cell migration. For the examination of cell invasion, the commercial transwell inserts (8 μm pore membrane) pre-loaded with Matrigel are incubated with serum-free medium in the presence or absence of BMS 777607 at 37 °C for 2 hours to allow rehydration of Matrigel. Then cells suspended in serum-free medium are loaded onto the top chamber (5 × 103/insert) and complete medium (containing 10% FBS) is used in the lower chamber as a chemoattractant. After incubation for 24 hours, the Matrigel is removed and the inserts are stained with crystal violet. Invaded cells on the underside of the filter are photographed and counted.

動物実験: [3]

動物モデル Rodent fibrosarcoma KHT cells are established in female C3H/HeJ mice.
製剤 Dissolved in DMSO as a stock solution (10 mM).
投薬量 10-25 mg/kg.
投与方法 Oral gavage once 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 BMS-777607 SDF
分子量 512.89
化学式

C25H19ClF2N4O4

CAS No. 1025720-94-8
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 47 mg/mL (91.63 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 4% DMSO+30% PEG 300+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-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

文献中の引用 (9)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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