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 Moi2T4lv[XOnIHHzd4F6 M2[wR2ROW09? NWj0W|F6cW6qaXLpeJMhVWW2IHvpcoF{\SC5aYToJGlEPTBib3[gNVAxKG6P MVexPVI3ODdzMR?=
H1993 M3S2PWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MmXDglExKM7:TR?= NFTWXGxFVVOR MXrJR|UxRTF3MDDuUS=> MofPNVkzPjB5MUG=
U87 MYjHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NGDpNHp,OTBizszN NH;4PW9FVVOR Mo\wTWM2OD1zNkCgcm0> M{LDZlE6OjZyN{Gx
PC-3 NF74R|NHfW6ldHnvckBie3OjeR?= MkXiNE4yKM7:TR?= M3K2WWROW09? MVjlfIhq[mm2czDpcohq[mm2b4L5JIVn\mWldDDvckBJT0ZvaX7keYNm\CClZXzsJJNk[XS2ZYLpcoc> MVOyNFUyPTl2Mx?=
DU145 M{[4cWZ2dmO2aX;uJIF{e2G7 MnzuNE4yKM7:TR?= Mor1SG1UVw>? MmK4[ZhpcWKrdIOgbY5pcWKrdH;yfUBm\m[nY4Sgc44hUEeILXnu[JVk\WRiY3XscEB{[2G2dHXybY5o M2TCZlIxPTF3OUSz
PC-3 NWm5R5dMTnWwY4Tpc44h[XO|YYm= M3\YSlAvODFizszN NYW0VJh3TE2VTx?= MlTMd5VxeHKnc4Pld{BJT0ZvaX7keYNm\CClZXzsJI1q\3KjdHnvci=> NHLUfXIzODVzNUm0Ny=>
DU145 NX7ZdFN5TnWwY4Tpc44h[XO|YYm= MnT0NE4xOSEQvF2= M3XBb2ROW09? NVHSOoxve3WycILld5NmeyCKR1[tbY5lfWOnZDDj[YxtKG2rZ4LheIlwdg>? NEix[m0zODVzNUm0Ny=>
PC-3 NXS5TpR2TnWwY4Tpc44h[XO|YYm= M4\ZU|AvOSEQvF2= NFzQSphFVVOR NUSzfItYcW2yYXnyd{BJT0ZvbXXkbYF1\WRiY3XscEBqdn[jc3nvci=> NWG1fohZOjB3MUW5OFM>
DU145 MWHGeY5kfGmxbjDhd5NigQ>? MXOwMlEh|ryP NHvyW5pFVVOR MnPEbY1x[Wm{czDIS2YudWWmaXH0[YQh[2WubDDpcpZie2mxbh?= NHnzeZMzODVzNUm0Ny=>
PC-3 M4rMWmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 Mm\4glExKM7:TR?= MkXGSG1UVw>? MXzy[YR2[2W|IHPlcIwheHKxbHnm[ZJifGmxbh?= NH7aSoozODVzNUm0Ny=>
KHT NGXrXmtMcW6jc3WgZZN{[Xl? MkfkSG1UVw>? NX;qeXZD[myxY3vzJJRp\SClLV3leEB{cWewYXzpcocheGG2aIfhfUB4cXSqIFnDOVAhd2ZiMUCgcm0> NVnQbm5mOjJ{OE[1NlM>
KHT NF3qOWdHfW6ldHnvckBie3OjeR?= M{i5fJ4yKM7:TR?= MoXjSG1UVw>? NWjKfms3eHKndnXueJMhe3CxboThcoVwfXNiS1jUJINmdGxic3PheJRmemmwZzD3bZRpKEmFNUCgc4YhOC5zLUCuOUDPxE1? NV6wOmpDOjJ{OE[1NlM>
KHT NVfNVYdwTnWwY4Tpc44h[XO|YYm= M1fjfJ4xNjVizszN MVzEUXNQ MnPVbY5pcWKrdIOgZ4VtdCCvaXfyZZRqd25? NF2yTnkzOjJ6NkWyNy=>
KHT MXvGeY5kfGmxbjDhd5NigQ>? NYrhbFlFhjBwNTFOwG0> NFnDU5dFVVOR NGTNXnZqdmirYnn0d{Bk\WyuIHnueoF{cW:w MVeyNlI5PjV{Mx?=
KHT MU\Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MVr+NVAh|ryP NVrOWlQ6TE2VTx?= NGLXPJhqdmirYnn0d{BMUFRiY3XscEBxem:uaX\ldoF1cW:w MoLRNlIzQDZ3MkO=
T-47D NIKzbXBIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M4TucZ42KM7:TR?= MmDpSG1UVw>? MYfpcohq[mm2czDj[YxtKHC{b3zp[oVz[XSrb36= M3TYUlI{PDZ6NUK5
ZR-75-1 M1H6PGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NIG4fm1,PSEQvF2= NFP3VZpFVVOR MnHRbY5pcWKrdIOgZ4VtdCCycn;sbYZmemG2aX;u MUWyN|Q3QDV{OR?=
T-47D M2HZR2Z2dmO2aX;uJIF{e2G7 M13pV|ExKM7:TR?= MUfEUXNQ MWXJcoR2[2W|IIDvcJlxdG:rZImgZpkhQDZiJR?= M2LWXlI{PDZ6NUK5
ZR-75-1 M2PCRmZ2dmO2aX;uJIF{e2G7 M1fHc|ExKM7:TR?= MkfJSG1UVw>? Mnm1TY5lfWOnczDwc4x6eGyxaXT5JIJ6KDh6JR?= NGnHelEzOzR4OEWyPS=>
T-47D NF;JTppHfW6ldHnvckBie3OjeR?= M4Ts[lExKM7:TR?= NFTpeJlFVVOR M2e0fYlvcGmkaYTzJGFWWktvQjDmeY5kfGmxbjDhcoQhcW6mdXPld{BqfHNicILveIVqdiCmZXfyZYRifGmxbh?= NU\rbIdUOjN2Nki1Nlk>
CHRF NWTxfY1nTnWwY4Tpc44h[XO|YYm= M3jLS|ExKM7:TR?= M1izRmROW09? MVHpcohq[mm2czDj[YxtKGSrdnnzbY9v NXXlOGtbOjV|MES5NFA>
HPDE NUPSdVdUTnWwY4Tpc44h[XO|YYm= NG\6dW8yOCEQvF2= MnnySG1UVw>? NW[5[Zd6[myxY3vzJINwdnO2aYT1eIl3\SCjY4TpeoF1cW:wIHHu[EBl\WO{ZXHz[YQhSUuWIIPp[45idGmwZx?= MWCyOlQ4PzNzNB?=
U118MG M4\SUmtqdmG|ZTDhd5NigQ>? NIjZcZJ,OyEQvF2= NHK5Vo9FVVOR M3KweIJtd2OtczDBXGwheGixc4Doc5J6dGG2aX;u MkHlNlY5PDh3MkS=
SF126 NILhSIZMcW6jc3WgZZN{[Xl? Mkj0glMh|ryP MUPEUXNQ M1iwPYJtd2OtczDBXGwheGixc4Doc5J6dGG2aX;u MnL4NlY5PDh3MkS=
U118MG MXzDfZRwgGmlaYT5JIF{e2G7 MV2xNk42KM7:TR?= NWr4UIFCTE2VTx?= M4DabYRm[3KnYYPld{BodGmxbXGgZ4VtdCC4aXHibYxqfHl? NHPuNYszPjh2OEWyOC=>
SF126 NHKzUHJEgXSxeHnjbZR6KGG|c3H5 NVjZbJFIOTJwNTFOwG0> Mn\ISG1UVw>? NEPjPGRl\WO{ZXHz[ZMh\2yrb33hJINmdGxidnnhZoltcXS7 M2qwfVI3QDR6NUK0
U118MG MnyzRZBweHSxc3nzJIF{e2G7 MomzNVIvPSEQvF2= NVWwNYlwTE2VTx?= NGPIZmdqdmS3Y3XzJIdtcW:vYTDj[YxtKGGyb4D0c5Nqew>? MY[yOlg1QDV{NB?=
SF126 MYTBdI9xfG:|aYOgZZN{[Xl? NYTONJdzOTJwNTFOwG0> Mkn2SG1UVw>? Mmq2bY5lfWOnczDncIlwdWFiY3XscEBieG:ydH;zbZM> NUXNUJlTOjZ6NEi1NlQ>
U118MG MXvGeY5kfGmxbjDhd5NigQ>? M2XhWVEzNjVizszN NX;3VYRvTE2VTx?= NEe3TVhjdG:la4Og[4xqd22jIHPlcIwhdWmpcnH0bY9vKGGwZDDpcpZie2m4ZTDndo94fGhicHH0eIVzdg>? NU\GTZdwOjZ6NEi1NlQ>
SF126 M2LVOmZ2dmO2aX;uJIF{e2G7 M{f0fFEzNjVizszN NVGwfXBmTE2VTx?= MlKwZoxw[2u|IHfsbY9u[SClZXzsJI1q\3KjdHnvckBidmRiaX72ZZNqfmViZ4Lve5RpKHCjdITldo4> MlrSNlY5PDh3MkS=

... 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 1% DMSO+30% polyethylene glycol+1% Tween 80 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 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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