PHA-665752 是一种选择性的 ATP 竞争活性位点c-Met激酶抑制剂,Ki为 4 nM,IC50为 9 nM。PHA-665752 对 c-Met 的选择性比一组不同的酪氨酸和丝氨酸苏氨酸激酶高 50 倍。PHA-665752 诱导细胞凋亡和细胞周期阻滞,具有细胞还原性抗肿瘤活性。
生物活性 | PHA-665752 is a selective, ATP-competitive, and active-site inhibitor of the catalytic activity ofc-Metkinase (Ki=4 nM;IC50=9 nM). PHA-665752 exhibits >50-fold selectivity for c-Met compared with a panel of diverse tyrosine and serine-threonine kinases. PHA-665752 inducesapoptosisand cell cycle arrest, and exhibits cytoreductive antitumor activity[1][2]. |
IC50& Target | Ki: 4 nM[1] IC50: 9 nM (c-Met)[1] |
体外研究 (In Vitro) | PHA-665752 is a potent and ATP-competitive inhibitor of c-Met kinase activity with a Kiof 4 nM and an IC50of 9 nM[1]. PHA-665752 exhibits >50-fold selectivity for c-Met enzyme compared with the majority of kinases evaluated[1]. PHA-665752 shows potent inhibition of c-Met RTK autophosphorylation in NIH3T3 cells engineered to express high levels of c-Met and hepatocyte growth factor (HGF)[1]. PHA-665752 inhibits HGF-stimulated or constitutive phosphorylation of mediators of downstream of c-Met such as Gab-1, ERK, Akt, STAT3, PLC-γ, and FAK in multiple tumor cell lines[1]. PHA-665752 (0-1.25 μM; 18 hours) potently inhibits HGF and c-Met-driven phenotypes such as cell growth (proliferation and survival), cell motility, invasion, and/or morphology of a variety of tumor cells[1]. PHA-665752 (0-1.25 μM; 72 hours) induces apoptosis in both the presence and absence of HGF at concentrations that inhibited tyrosine phosphorylation of c-Met in GTL-16 cells[1]. PHA-665752 (0.0125-0.2 μM; 4 hours) potent inhibits HGF-induced c-Met phosphorylation in A549 cells[1].
Cell Proliferation Assay[1] Cell Line: | S114 cells, GTL-16 cells, NCI-H441 cells, or BxPC-3 cells | Concentration: | 0 μM, 0.002 μM, 0.01 μM, 0.05 μM, 0.25 μM, 1.25 μM | Incubation Time: | 18 hours | Result: | Potently inhibited HGF and c-Met-driven cell growth. |
Apoptosis Analysis[1] Cell Line: | GTL-16 cells | Concentration: | 0 μM, 0.002 μM, 0.01 μM, 0.05 μM, 0.25 μM, 1.25 μM | Incubation Time: | 72 hours | Result: | Induced apoptosis in both the presence and absence of HGF at concentrations that inhibited tyrosine phosphorylation of c-Met in GTL-16 cells. Immunoblot Analysis. |
Western Blot Analysis[1] Cell Line: | A549 cells | Concentration: | 0.0125 μM, 0.025 μM,0.05 μM,0.1 μM,0.2 μM | Incubation Time: | 4 hours | Result: | Potent inhibited HGF-induced c-Met phosphorylation in A549 cells. |
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体内研究 (In Vivo) | PHA-665752 (7.5-30 mg/kg/day; i.v. ; for 9 days) exhibits statistically significant dose-dependent tumor growth inhibition of 68%, 39%, and 20% of vehicle control at the 30 mg/kg/day, 15 mg/kg/day, and 7.5 mg/kg/day doses, respectively[1]. PHA-665752 shows a potent cytoreductive activity in a gastric carcinoma xenograft model[1].
Animal Model: | Female athymic mice (nu/nu, 8–12 weeks) bearing S114 or GTL-16 tumor xenografts[1] | Dosage: | 7.5 mg/kg/day, 15 mg/kg/day, 30 mg/kg/day | Administration: | Intravenous injection; for 9 days | Result: | Demonstrated statistically significant dose-dependent tumor growth inhibition. |
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运输条件 | Room temperature in continental US; may vary elsewhere. |
储存方式 | Powder | -20°C | 3 years | | 4°C | 2 years | In solvent | -80°C | 6 months | | -20°C | 1 month |
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溶解性数据 | In Vitro: DMSO : 25 mg/mL(38.96 mM;Need ultrasonic) 配制储备液 1 mM | 1.5586 mL | 7.7929 mL | 15.5858 mL | 5 mM | 0.3117 mL | 1.5586 mL | 3.1172 mL | 10 mM | 0.1559 mL | 0.7793 mL | 1.5586 mL |
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以下溶剂前显示的百 分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂: 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.5 mg/mL (3.90 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (3.90 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂: 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: 2.5 mg/mL (3.90 mM); Suspended solution; Need ultrasonic
此方案可获得 2.5 mg/mL (3.90 mM) 的均匀悬浊液,悬浊液可用于口服和腹腔注射。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。 3. 请依序添加每种溶剂: 10% DMSO 90%corn oil Solubility: ≥ 2.5 mg/mL (3.90 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (3.90 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。 *以上所有助溶剂都可在本网站选购。
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