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BMS 777607

产品号 S1561 公司名称 Selleck Chemicals
CAS号 1196681-44-3 公司网站 http://www.selleckchem.com
分子式 C25H19ClF2N4O4 电 话 (877) 796-6397
分子量 512.8925664 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72746

产品价格信息

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产品别名

标题
BMS 777607
IUPAC标准名
N-{4-[(2-amino-3-chloropyridin-4-yl)oxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
IUPAC传统名
N-{4-[(2-amino-3-chloropyridin-4-yl)oxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide
别名
BMS-777607
BMS777607

产品登记号

CAS号 1196681-44-3

产品性质

作用靶点 MEK
成盐信息 Free Base
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, respectively.
Targets c-Met Axl Ron Tyro3
IC50 3.9 nM 1.1 nM 1.8 nM 4.3 nM [1]
In Vitro 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 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 ± 14.9 %, P<0.001), 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]
Clinical Trials 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 type I papillary renal cell carcinoma.
Features BMS 777607 is a potent inhibitor of Met family member, which is more than 40-fold selective versus Lck, VEGFR2, and TrkA/B and more than 500-fold selective versus all other receptor and nonreceptor kinases.
Protocol
Kinase Assay [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.
Cell Assay [3]
Cell Lines Rodent fibrosarcoma KHT cells
Concentrations Dissolved in DMSO as a stock solution (10 mM), final concentration ~10 μM.
Incubation Time 2, 24 and 96 hours
Methods 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.
Animal Study [3]
Animal Models Rodent fibrosarcoma KHT cells are established in female C3H/HeJ mice.
Formulation Dissolved in DMSO as a stock solution (10 mM).
Doses 10-25 mg/kg.
Administration Oral gavage once daily.
References
[1] Schroeder GM, et al. J Med Chem, 2009, 52(5), 1251-1254.
[2] Dai Y, et al. Mol Cancer Ther, 2010, 9(6), 1554-1561.
[3] Dai Y, et al. Clin Exp Metastasis, 2012, 29, 253-261.
[4] Kim KS, et al. J Med Chem, 2008, 51(17), 5330-5341.