化合物BMS-777607 T2699

Product Introduction
Bioactivity


英文名: BMS 777607

描述: BMS 777607 (BMS 817378) 是 Met-related 抑制剂，能够抑制 c-Met (IC50:3.9 nM)，Axl (IC50:1.1 nM)，Ron (IC50:1.8 nM) 和 Tyro3 (IC50:4.3 nM) 的活性。

细胞实验: 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. (Only for Reference)

激酶实验: 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.

体外活性: 在携带GTL-16人类移植瘤的无胸腺小鼠中,BMS-777607（6.25-50 mg/kg,p.o.）可无毒性地显著降低肿瘤体积.BMS 777607（10 mg/kg）也可一定程度抑制肺结节形成.在6-8周大的注射啮齿类纤维肉瘤KHT细胞的雌性C3H/HeJ小鼠体内,BMS-777607（25 mg/kg/day）降低KHT肺肿瘤结节数量,提高形态出血,且明显修复损害转移表型,且无明显毒性.

体内活性: BMS-777607不太影响肿瘤细胞生长,在PC-3和DU145 细胞中,其对肝细胞生长因子诱导的细胞分散有抑制作用,其还剂量依赖性抑制细胞迁移和入侵（IC50<0.1 μM）。BMS-777607是选择性ATP竞争Met激酶抑制剂,对c-Met自磷酸化有较强抑制,对GTL-16细胞裂解物的IC50为20 nM,且对Met驱动的肿瘤细胞系如GTL-16细胞系,H1993和 U87细胞的增殖有选择性抑制作用。在DU145前列腺癌细胞中,BMS-777607对肝细胞生长因子 (HGF)引起的c-Met自磷酸化有抑制作用（IC50<1 nM）。BMS-777607（1 μM）处理24 h,有效抑制KHT细胞分散、活动和入侵,这与MET基因抑制相关,且对细胞增殖和集落形成有一定影响。在高度转移性鼠科KHT细胞中,BMS-777607（10 μM）处理2 h,有效清除自磷酸化的c-Met水平（IC50：10 nM）,不影响全部c-Met,从而剂量依赖性地抑制下游信号分子包括 ERK, Akt, p70S6K 和 S6。

存储条件: Powder: -20°C for 3 years | In solvent: -80°C for 1 year

溶解度: Ethanol : < 1 mg/mL (insoluble or slightly soluble)
H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 44 mg/mL (85.8 mM)


关键字: c-Met/HGFR | Inhibitor | Mer | inhibit | Axl | TAM Receptor | BMS 777607 | Tyro3 | BMS-817378 | BMS817378

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注：该产品未在中华人民共和国食品药品监督管理部门申请医疗器械注册和备案，不可用于临床诊断或治疗等相关用途