| 名称 | azd1390 |
| 描述 | AZD1390 is an exceptionally potent inhibitor of ATM in cells (IC50: 0.78 nM) with >10,000-fold selectivity over closely related members of the PIKK family of enzymes. |
| 细胞实验 | Cells were seeded in six-well plates to a density of 50 to 60% and incubated at 37°C for 24 hours. Cells were pretreated with AZD1390, the ATR inhibitor AZD6738, the Wee1 inhibitor AZD1775, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib, or the DNA-PK inhibitor KU-0060648 at indicated concentrations for 1 hour and subsequently irradiated at 2 Gy using the Faxitron CellRad (130-kV, 5-mA, 0.5-mm Al). In washout experiments, the cell culture medium was immediately replaced and cells were incubated with or without the compound for 1, 6, and 24 hours. In all other experiments, proteins were collected at indicated time points following irradiation. Proteins were harvested by scraping the cells in radioimmunoprecipitation assay (RIPA) lysis buffer supplemented with protease and phosphatase inhibitors. Protein content was quantified using the BCA Protein Assay Kit according to manufacturing conditions. Proteins were separated by SDS–polyacrylamide gel electrophoresis on 4 to 12% bis-tris or 3 to 8% Tris-acetate gels and transferred onto nitrocellulose membranes using the iBlot Dry Blotting System. Membranes were briefly washed with water and Tris-buffered saline (TBS) with 0.05% Tween 20 (TBST) once and incubated in blocking solution, followed by primary antibodies diluted in TBST with 5% (w/v) nonfat dry milk or 3% bovine serum albumin (BSA) overnight at 4°C with shaking. Membranes were then washed three times and incubated for 1.5 hours with horseradish peroxidase (HRP)–conjugated antibodies and/or LI-COR fluorescent antibodies CW700-800 in TBST with 5% (w/v) nonfat dry milk. Membranes were washed five times with TBST, and proteins were visualized with the Fuji or Syngene G:BOX Imaging System or Film Developer after enhanced chemiluminescence substrate addition. |
| 动物实验 | Bioluminescence signaling of implanted 3 × 10^5 NCI-H2228-Luc cells was measured using an IVIS Xenogen imaging machine to monitor tumor growth. When the signal reached the range of 10^7 to 10^8, the mice were randomized into different treatment groups and treated orally with either vehicle or AZD1390 QD or BID + IR at 2.5 Gy daily for four consecutive days. AZD1390 or vehicle was dosed at 1 hour before IR on each dosing day. The bioluminescence signals and body weight of the mice were measured once weekly, and the raw data were recorded according to their study number and measurement date in the in vivo database. TGI from the start of treatment was assessed by comparison of the mean change in bioluminescence intensity for the control and treated groups and presented as % of TGI. The calculation of inhibition and regression was based on the geometric mean of relative tumor volume (RTV) in each group. "CG" means the geometric mean of RTV of the control group, whereas "TG" means the geometric mean of RTV of the treated group. On specific day, for each treated group, the inhibition value was calculated using the following formula: Inhibition% = (CG ? TG) * 100/(CG ? 1). CG should use the corresponding control group of the treated group during calculation. If inhibition was >100%, then regression was calculated using the following formula: Regression = 1 – TG. Statistical significance was evaluated using a one-tailed t-test. Survival benefit was measured by Kaplan-Meier plots at the end of the study. |
| 体外活性 | AZD1390对ATM自磷酸化的抑制在治疗后4小时发生，3 nM在LN18 GBM细胞中产生了强烈的ATM抑制效果。在相同条件下测试的其他DDR抑制剂，即便是在相关IC50浓度下，也未对pATM水平产生影响。在使用AZD1390及2 Gy辐射处理24小时后，观察到G2阶段累积量呈剂量依赖性增加，这表明细胞没有在S期停滞，而是在G2阶段累积或在有丝分裂过程中遇到问题。 |
| 体内活性 | 在体内同源和患者来源的胶质瘤模型以及原位肺脑转移模型中，AZD1390与每日分割的IR（全脑或立体定向放射治疗）联合使用，显著促进了肿瘤退缩并提高了动物存活率。 |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 4.77 mg/mL (9.98 mM), Sonication is recommended.
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| 关键字 | azd1390 | ATM/ATR | azd-1390 | ATM and RAD3 related | AZD 1390 | inhibit | Inhibitor | Ataxia telangiectasia mutated |
| 相关产品 | Schisandrin B | Ceralasertib | AZ31 | Berzosertib | KU60019 | Elimusertib | CP-466722 | GJ103 sodium salt | Ro 90-7501 | NU6027 | (Z)-Mirin | Dactolisib |
| 相关库 | 抑制剂库 | 经典已知活性库 | 抗癌活性化合物库 | 已知活性化合物库 | 激酶抑制剂库 | 高选择性抑制剂库 | 酪氨酸激酶分子库 | 药物功能重定位化合物库 | 抗癌临床化合物库 | 抗癌药物库 |
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