| 名稱 | BMS 777607 |
| 描述 | BMS 777607 (BMS 817378) is a Met-related inhibitor for c-Met/Axl/Ron/Tyro3 (IC50: 3.9/1.1/1.8/4.3 nM). BMS-777607 has been investigated for the basic science of Malignant Solid Tumour. |
| 細(xì)胞實(shí)驗(yàn) | 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) |
| 激酶實(shí)驗(yàn) | 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. |
| 體外活性 | 在攜帶GTL-16人類移植瘤的無胸腺小鼠中,BMS-777607（6.25-50 mg/kg,p.o.）可無毒性地顯著降低腫瘤體積.BMS 777607（10 mg/kg）也可一定程度抑制肺結(jié)節(jié)形成.在6-8周大的注射嚙齒類纖維肉瘤KHT細(xì)胞的雌性C3H/HeJ小鼠體內(nèi),BMS-777607（25 mg/kg/day）降低KHT肺腫瘤結(jié)節(jié)數(shù)量,提高形態(tài)出血,且明顯修復(fù)損害轉(zhuǎn)移表型,且無明顯毒性. |
| 體內(nèi)活性 | BMS-777607不太影響腫瘤細(xì)胞生長(zhǎng),在PC-3和DU145 細(xì)胞中,其對(duì)肝細(xì)胞生長(zhǎng)因子誘導(dǎo)的細(xì)胞分散有抑制作用,其還劑量依賴性抑制細(xì)胞遷移和入侵（IC50<0.1 μM）。BMS-777607是選擇性ATP競(jìng)爭(zhēng)Met激酶抑制劑,對(duì)c-Met自磷酸化有較強(qiáng)抑制,對(duì)GTL-16細(xì)胞裂解物的IC50為20 nM,且對(duì)Met驅(qū)動(dòng)的腫瘤細(xì)胞系如GTL-16細(xì)胞系,H1993和 U87細(xì)胞的增殖有選擇性抑制作用。在DU145前列腺癌細(xì)胞中,BMS-777607對(duì)肝細(xì)胞生長(zhǎng)因子 (HGF)引起的c-Met自磷酸化有抑制作用（IC50<1 nM）。BMS-777607（1 μM）處理24 h,有效抑制KHT細(xì)胞分散、活動(dòng)和入侵,這與MET基因抑制相關(guān),且對(duì)細(xì)胞增殖和集落形成有一定影響。在高度轉(zhuǎn)移性鼠科KHT細(xì)胞中,BMS-777607（10 μM）處理2 h,有效清除自磷酸化的c-Met水平（IC50：10 nM）,不影響全部c-Met,從而劑量依賴性地抑制下游信號(hào)分子包括 ERK, Akt, p70S6K 和 S6。 |
| 存儲(chǔ)條件 | keep away from moisture,store at low temperature | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 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)
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| 關(guān)鍵字 | c-Met/HGFR | Inhibitor | Mer | inhibit | Axl | TAM Receptor | BMS 777607 | Tyro3 | BMS-817378 | BMS817378 |
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| 相關(guān)庫 | 抗乳腺癌化合物庫 | 細(xì)胞因子抑制劑庫 | 抗結(jié)直腸癌化合物庫 | ReFRAME 相關(guān)化合物庫 | 激酶抑制劑庫 | 含氟化合物庫 | NO PAINS 化合物庫 | 抗肺癌化合物庫 | 酪氨酸激酶分子庫 | 細(xì)胞重編程化合物庫 |