| 名稱 | AZD3759 hydrochloride |
| 描述 | AZD3759 (hydrochloride) is an effective, orally active and central nervous system-penetrant EGFR inhibitor. At Km ATP concentrations, the IC50s are 0.2/0.3/0.2 nM for EGFR (L858R)/EGFR (wt)/EGFR (exon 19Del). |
| 細(xì)胞實驗 | AZD3759 is prepared in DMSO and stored,and then diluted with the appropriate medium before use[1].Cell proliferation assay is determined by MTS methods.Briefly,cells are seeded in 96-well plates (at a density to allow for logarithmic growth during the 72-hour assay) and incubated overnight at 37°C and 5% CO2.Cells are then exposed to concentrations of compounds (e.g.,AZD3759) ranging from 30 mM to 0.3 μM for 72 hours.For the MTS endpoint,cell proliferation is measured by the CellTiter AQueous Non-Radioactive Cell Proliferation Assay reagent.Absorbance is measured with a Tecan Ultra instrument.Predose measurements are made,and concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) values are determined using absorbance readings[1]. |
| 激酶實驗 | AZD3759 is tested at a single 1 μM concentration across each of 124 kinases from Millipore kinase panel at an ATP concentration that is within 15 μM of their corresponding apparent Km values. In brief, recombinant kinases are incubated within an appropriate buffer containing peptide substrate and radiolabelled γ-33P-ATP together with presence or absence of required inhibitor concentration. The reaction is initiated by adding ATP/Mg2+ mix. After incubation for 40 minutes at room temperature, the reaction is stopped by adding 3% phosphoric acid solution. A portion of reaction mix is spotted onto P30 filter mat to trap peptide and washed three times for 5 minutes with phosphoric acid to remove non-specific γ-33P-ATP. The phosphorylated substrate is then measured by scintillation counting, which determined the level of kinase activity inhibition compared to control reactions[1]. |
| 動物實驗 | AZD3759 is prepared in 1% methylcellulose (Rat)[1].Male Han Wistar rats are orally dosed with the AZD3759 at 2 mg/kg in 1% methylcellulose. At 0.25, 0.5, 1, 2, 4 and 7 hour post-dose, cerebral spinal fluid (CSF) is collected from cisterna magna, and blood samples (>60 μL/time point/each site) are collected via cardiac puncture, into separate EDTA coagulated tubes, and then immediately diluted with 3-fold volume of water. Brain tissue is harvested and homogenized in 3x volume of 100 mM phosphate buffered saline (pH7.4). All samples are stored at -70°C prior to LC/MS/MS analysis. |
| 體外活性 | 在2 mM的ATP濃度下，EGFR (wt)/EGFR (L858R)/EGFR (exon 19Del)的IC50分別為102/7.6/2.4 nM。AZD3759還可針對pEGFR進(jìn)行抑制，在H838wt、H3255L858R、PC-9exon 19Del中的IC50分別為64.5 nM、7.2 nM和7.4 nM。在細(xì)胞磷酸化研究中，AZD3759還展示了對激活突變EGFR細(xì)胞株相比于EGFR野生型細(xì)胞株（H838細(xì)胞系）的9倍選擇性抑制作用[1]。 |
| 體內(nèi)活性 | 在大鼠中，AZD3759（2 mg/kg，口服）的吸收迅速，血液Cmax達(dá)到0.58 μM，于1.0小時實現(xiàn)。隨后，AZD3759的血液濃度以平均消除半衰期4.3小時單指數(shù)下降，與通過靜脈注射得到的4.1小時的參數(shù)相近。大鼠口服后的生物利用度為91%。在狗進(jìn)行靜脈注射后，AZD3759的血液清除率為14 mL/min/kg，分布容積為6.4 L/kg，其消除半衰期為6.2小時。AZD3759的吸收迅速，血液Cmax（698 nM）在0.5至1.5小時之間出現(xiàn)。AZD3759的口服生物利用度極佳，為90%。AZD3759表現(xiàn)出顯著的劑量依賴性抗腫瘤效能（在治療后4周，7.5 mg/kg/天和15 mg/kg/天分別實現(xiàn)了78%的腫瘤生長抑制和腫瘤退縮），且體重?fù)p失<20%。AZD3759（7.5/15 mg/kg）能顯著減少腫瘤面積。此外，在服用單劑量AZD3759（15 mg/kg）1小時后，通過檢測到pEGFR的調(diào)節(jié)[1]。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 50 mg/mL (100.73 mM), Sonication is recommended.
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| 關(guān)鍵字 | EGFR (wt) | EGFR (L858R) | EGFR (exon 19De) | AZD-3759 Hydrochloride | AZD-3759 hydrochloride | AZD3759 hydrochloride | AZD3759 Hydrochloride | AZD 3759 Hydrochloride |
| 相關(guān)產(chǎn)品 | Lapatinib | Neratinib | Chalcone | Gefitinib | Erlotinib | Osimertinib | Erlotinib hydrochloride | Afatinib Dimaleate | Lidocaine Hydrochloride hydrate | Genistein | Khellin | Osimertinib mesylate |
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