BMS-777607 化学構造
分子量: 512.89

高品質保証

カスタマーフィードバック(6)

Quality Control & MSDS

製品説明

  • Compare c-Met Inhibitors
    c-Met製品生物活性の比較
  • 研究分野
  • BMS-777607のメカニズム

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]
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)


Click to enlarge
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.

Click to enlarge
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.

Click to enlarge
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.

Click to enlarge
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.

Click to enlarge
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.

文献中の引用 (8)

技術サポート&よくある質問(FAQ)

ストックの作り方、阻害剤の保管する方法、細胞実験や動物実験に注意すべきな点を全部含めており、製品を取扱う時よくあった質問に対して取扱説明書でお答えいたします。

電話番号: +1-832-582-8158 Ext:3月曜日〜金曜日 9:00 AM–5:00 PM (米国中部標準時)

他の質問がある場合は、お気軽くお問合せください。

* 必須

Related c-Met 阻害剤

  • NPS-1034

    NPS-1034 is a dual Met/Axl inhibitor with IC50 of 48 nM and 10.3 nM, respectively.

  • Erlotinib

    Erlotinib is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.

  • R428 (BGB324)

    R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).

  • BLZ945

    BLZ945 is an orally active, potent and selective CSF-1R inhibitor with IC50 of 1 nM, >1000-fold selective against its closest receptor tyrosine kinase homologs.

  • Crizotinib (PF-02341066)

    Crizotinib (PF-02341066) は1種の有効な小分子の卵白の阻害剤の再編人プロテインキナーゼ、 Kiが 4 nM。

  • Foretinib (GSK1363089)

    Foretinib (GSK1363089)は、目標が会ったATP競争的活性部位阻害剤とKDRで、IC50がそれぞれ0.4 nM と 0.9 nMです。

  • SU11274

    SU11274は、10nMのIC50による選択的なMetチロシン・キナーゼ阻害剤です。

  • Capmatinib (INCB28060)

    Capmatinib (INCB28060)は、IC50が0.13nMによりあるc-METキナーゼの新しい、ATP競争的阻害剤です。

    Features:Inactive against RONβ, another member of the c-MET RTK family, as well as EGFR and HER-3 (members of the EGFR RTK family).

  • PHA-665752

    PHA-665752は、9nMのIC50による強力で、選択的で、ATP競争的c-Met阻害剤です。

最近チェックしたアイテム

Tags: BMS-777607を買う | BMS-777607供給者 | BMS-777607を購入する | BMS-777607費用 | BMS-777607生産者 | オーダーBMS-777607 | BMS-777607代理店
×
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
お問い合わせ