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 NXzq[|hyU2mwYYPlJIF{e2G7 NV3zb5VqTE2VTx?= MUTpcohq[mm2czDN[ZQhc2mwYYPlJJdqfGhiSVO1NEBw\iBzMECgcm0> MoDXNVkzPjB5MUG=
H1993 MX3Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NFvUe4J,OTBizszN NXzWWIpXTE2VTx?= MVjJR|UxRTF3MDDuUS=> MXexPVI3ODdzMR?=
U87 M{PSPGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NVXjXXJbhjFyIN88US=> NWPKTIN4TE2VTx?= MoKwTWM2OD1zNkCgcm0> M2LkNFE6OjZyN{Gx
PC-3 MYjGeY5kfGmxbjDhd5NigQ>? NYrSbFN4OC5zIN88US=> MkTKSG1UVw>? MmnE[ZhpcWKrdIOgbY5pcWKrdH;yfUBm\m[nY4Sgc44hUEeILXnu[JVk\WRiY3XscEB{[2G2dHXybY5o M4j6S|IxPTF3OUSz
DU145 NYL4TYNETnWwY4Tpc44h[XO|YYm= Mk\qNE4yKM7:TR?= NE\qO5NFVVOR MlPu[ZhpcWKrdIOgbY5pcWKrdH;yfUBm\m[nY4Sgc44hUEeILXnu[JVk\WRiY3XscEB{[2G2dHXybY5o NIPFS|IzODVzNUm0Ny=>
PC-3 M1zPU2Z2dmO2aX;uJIF{e2G7 Mk[xNE4xOSEQvF2= MWLEUXNQ M3jjVZN2eHC{ZYPz[ZMhUEeILXnu[JVk\WRiY3XscEBucWe{YYTpc44> MV:yNFUyPTl2Mx?=
DU145 NUH0NpEyTnWwY4Tpc44h[XO|YYm= NYLa[HYyOC5yMTFOwG0> MkPQSG1UVw>? MmDXd5VxeHKnc4Pld{BJT0ZvaX7keYNm\CClZXzsJI1q\3KjdHnvci=> MXiyNFUyPTl2Mx?=
PC-3 M3zKemZ2dmO2aX;uJIF{e2G7 NH\w[G8xNjFizszN MoLySG1UVw>? M{fhZYlueGGrcoOgTGdHNW2nZHnheIVlKGOnbHygbY53[XOrb36= NYHVR4pWOjB3MUW5OFM>
DU145 NF7OOpVHfW6ldHnvckBie3OjeR?= NF23[mExNjFizszN MVfEUXNQ M{G2TIlueGGrcoOgTGdHNW2nZHnheIVlKGOnbHygbY53[XOrb36= MlzzNlA2OTV7NEO=
PC-3 NVXSdGMxT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MVr+NVAh|ryP NVTEZZN5TE2VTx?= M3O1d5Jm\HWlZYOgZ4VtdCCycn;sbYZmemG2aX;u MWiyNFUyPTl2Mx?=
KHT NXLHN5pOU2mwYYPlJIF{e2G7 Mlr2SG1UVw>? MVHicI9kc3NidHjlJIMuVWW2IIPp[45idGmwZzDwZZRpf2G7IIfpeIghUUN3MDDv[kAyOCCwTR?= M2LoSVIzOjh4NUKz
KHT NFjIc3VHfW6ldHnvckBie3OjeR?= Mlj6glEh|ryP M4TXXGROW09? NVX1dlg{eHKndnXueJMhe3CxboThcoVwfXNiS1jUJINmdGxic3PheJRmemmwZzD3bZRpKEmFNUCgc4YhOC5zLUCuOUDPxE1? M1y4WlIzOjh4NUKz
KHT MnnqSpVv[3Srb36gZZN{[Xl? MYj+NE42KM7:TR?= NUnne4VGTE2VTx?= Mn\rbY5pcWKrdIOgZ4VtdCCvaXfyZZRqd25? M1H3ZVIzOjh4NUKz
KHT MVzGeY5kfGmxbjDhd5NigQ>? NVjVUlZuhjBwNTFOwG0> NHTkc4ZFVVOR Mkm1bY5pcWKrdIOgZ4VtdCCrbo\hd4lwdg>? NX30c5oxOjJ{OE[1NlM>
KHT M{TObmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MmL0glExKM7:TR?= MkjqSG1UVw>? M1rJeolvcGmkaYTzJGtJXCClZXzsJJBzd2yrZnXyZZRqd25? NYf4WoZqOjJ{OE[1NlM>
T-47D NFLTW41Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NX3wV|NohjVizszN NIPKXIFFVVOR Mm\KbY5pcWKrdIOgZ4VtdCCycn;sbYZmemG2aX;u MknvNlM1Pjh3Mkm=
ZR-75-1 NI[yUlFIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NHPBVnd,PSEQvF2= NGDkOGZFVVOR M{\OUolvcGmkaYTzJINmdGxicILvcIln\XKjdHnvci=> MVWyN|Q3QDV{OR?=
T-47D M2La[mZ2dmO2aX;uJIF{e2G7 NVHzOnZlOTBizszN MVLEUXNQ MofTTY5lfWOnczDwc4x6eGyxaXT5JIJ6KDh4IDW= M3TzPFI{PDZ6NUK5
ZR-75-1 MV\GeY5kfGmxbjDhd5NigQ>? MUKxNEDPxE1? M2jOSmROW09? Ml\3TY5lfWOnczDwc4x6eGyxaXT5JIJ6KDh6JR?= MXqyN|Q3QDV{OR?=
T-47D MknzSpVv[3Srb36gZZN{[Xl? MoD1NVAh|ryP Mn22SG1UVw>? M4niNIlvcGmkaYTzJGFWWktvQjDmeY5kfGmxbjDhcoQhcW6mdXPld{BqfHNicILveIVqdiCmZXfyZYRifGmxbh?= M1L4dlI{PDZ6NUK5
CHRF MmLiSpVv[3Srb36gZZN{[Xl? NXS1PW9GOTBizszN MXvEUXNQ MnvCbY5pcWKrdIOgZ4VtdCCmaY\pd4lwdg>? M{\LWVI2OzB2OUCw
HPDE NUXMbXlHTnWwY4Tpc44h[XO|YYm= NWS2Z2ZwOTBizszN NHTVTYlFVVOR MYLicI9kc3NiY3;ud5RqfHW2aY\lJIFkfGm4YYTpc44h[W6mIHTlZ5Jm[XOnZDDBT3Qhe2mpbnHsbY5o MUeyOlQ4PzNzNB?=
U118MG MlnyT4lv[XOnIHHzd4F6 M3jLVZ4{KM7:TR?= NInOW49FVVOR M4foNoJtd2OtczDBXGwheGixc4Doc5J6dGG2aX;u NVXlb3JQOjZ6NEi1NlQ>
SF126 MWjLbY5ie2ViYYPzZZk> NVTQZWRIhjNizszN NEDqfGZFVVOR MXficI9kc3NiQWjMJJBpd3OyaH;yfYxifGmxbh?= MmWwNlY5PDh3MkS=
U118MG NV73bYJkS3m2b4jpZ4l1gSCjc4PhfS=> MkOwNVIvPSEQvF2= NXTXO4hrTE2VTx?= M1zXUIRm[3KnYYPld{BodGmxbXGgZ4VtdCC4aXHibYxqfHl? MWSyOlg1QDV{NB?=
SF126 MVrDfZRwgGmlaYT5JIF{e2G7 MWixNk42KM7:TR?= NYDWOplLTE2VTx?= Mki0[IVkemWjc3XzJIdtcW:vYTDj[YxtKH[rYXLpcIl1gQ>? MoDpNlY5PDh3MkS=
U118MG NXSxfZI{SXCxcITvd4l{KGG|c3H5 MXSxNk42KM7:TR?= MlPvSG1UVw>? MULpcoR2[2W|IHfsbY9u[SClZXzsJIFxd3C2b4Ppdy=> NFjxPFgzPjh2OEWyOC=>
SF126 MWXBdI9xfG:|aYOgZZN{[Xl? MYCxNk42KM7:TR?= NFrWUmhFVVOR NY[xV5E2cW6mdXPld{BodGmxbXGgZ4VtdCCjcH;weI9{cXN? M1zpOVI3QDR6NUK0
U118MG M{fjc2Z2dmO2aX;uJIF{e2G7 MkHmNVIvPSEQvF2= MUHEUXNQ M33L[oJtd2OtczDncIlwdWFiY3XscEBucWe{YYTpc44h[W6mIHnueoF{cX[nIHfyc5d1cCCyYYT0[ZJv NUjl[4dWOjZ6NEi1NlQ>
SF126 NFzPSIxHfW6ldHnvckBie3OjeR?= NYjVdoZtOTJwNTFOwG0> NYXwfpNTTE2VTx?= M1fV[IJtd2OtczDncIlwdWFiY3XscEBucWe{YYTpc44h[W6mIHnueoF{cX[nIHfyc5d1cCCyYYT0[ZJv MUKyOlg1QDV{NB?=

... 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

カスタマーフィードバック (6)


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Rating
Source Mol Cancer Ther, 2014, 13(1), 37-48. BMS-777607 purchased from Selleck
Method Clonogenic growth assay
Cell Lines L3.6pl cells and CSCs+24/44/ESA
Concentrations 0-5 μM
Incubation Time 12 d
Results More than 70% reduction in colonogenic growth wasobserved when BMS-777607 was used at 5 μmol/L.

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Rating
Source Mol Cancer Ther, 2014, 13(1), 37-48. BMS-777607 purchased from Selleck
Method Clonogenic assay
Cell Lines L3.6pl and CSCs+24/44/ESA
Concentrations 0-5 uM
Incubation Time 12 d
Results The inhibitory effect of BMS-777607 onsurvival and proliferation of L3.6pl and CSCs+24/44/ESAwas determined by the clonogenic assay. Briefly, L3.6pl cells (6,000 cells/well) in minimum essential media (MEM) with 5% FBS were cultured in duplicate in a 24-well plate and then treated with different amounts of BMS-777607 for 12 days.CSCs+24/44/ESA in stem cell culture media were incubated for 18 days in the ultra-low attachment culture plate coated with a thin layer of 0.2% of agarose tofacilitate cell anchored growth. Clonogenic cells were stained with Hema-3 staining solution (Fisher Scienti fi c), photographed using an Olympus BK71microscope equipped with CCD camera, and counted. The number of clonogenic growth from individual groups is presented.

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Rating
Source Mol Oncol, 2013, 10.1016/j.molonc.2013.12.014. BMS-777607 purchased from Selleck
Method immunofluorescent analysis
Cell Lines T-47D and ZR-75-1 cells
Concentrations 5 uM
Incubation Time 72 h
Results Abnormal accumulation of survivin and its disassociation with condensed DNA and mitotic spindle. Both T-47D and ZR-75-1 cells were treated with 5 μM BMS-777607 for 72 h followed by immunofluorescent analysis using antibodies specific to survivin and a-tubulin. Cells were also stained with DAPI for nuclear DNA.

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Rating
Source Mol Oncol, 2013, 8, 469-82. BMS-777607 purchased from Selleck
Method immunofluorescent analysis
Cell Lines T-47D and ZR-75-1 cells
Concentrations 5 uM
Incubation Time 3 d
Results BMS-777607 increases p21/WAF1 and survivin expression but down-regulates Rb expression. T-47D and ZR-75-1 cells (2×106 cells in 60 mm diameter culture dish) were treated with 5 mM BMS-777607 for different time intervals. Cellular proteins (50 mg per sample) from cell lysates were subjected to Western blot analysis using individual antibodies specific to p53, p21/WAF1, survivin, regular and phospho-Rb. B-actin was used as the loading control.

Click to enlarge
Rating
Source Acta Pharmacol Sin, 2013, 34, 1545-53. BMS-777607 purchased from Selleck
Method clonogenic assay
Cell Lines T-47D, ZR-751, and MCF-7 Cells
Concentrations 1, 2.5, 5 uM
Incubation Time 10 d
Results Effect of BMS-777607 on growth and survival of breast cancer cells. A, the effect of BMS-777607 on survival and proliferation of MCF-7, ZR-75-1, and T-47D cells was determined by clonogenic assay. Briefly, cells (8,000 cells per well) in RPMI-1640 with 5% FBS were cultured in duplicate in a 24-well plate and then treated with different amounts of BMS-777607 for 10 days. Clonogenic cells were stained with Hema-3 staining solution (Fisher Scientific) and photographed using an Olympus BK71 microscope equipped with CCD camera. B, numbers of clonogenic cells in duplicate from 3 cell lines were counted.

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Rating
Source 2014, Dr.Wang from Southern Medical Hospital. BMS-777607 purchased from Selleck
Method Western blot
Cell Lines A549 cells
Concentrations 0-10 uM
Incubation Time 2 h
Results Effect of MEK inhibitor BMS-777607 in A549 cells. A549 cells were incubated with increasing concentrations of BMS-777607 for 2 h. The cell lysates were harvested and phosphorylation of indicated proteins was determined by Western blotting.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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