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AZD3759 (Synonyms: AZD3759)

カタログ番号GC13143

AZD3759 (AZD3759) は、強力な経口活性のある中枢神経系浸透性の EGFR 阻害剤です。 Km ATP 濃度では、EGFRwt、EGFRL858R、および EGFRexon 19Del の IC50 は、それぞれ 0.3、0.2、および 0.2 nM です。

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AZD3759 化学構造

Cas No.: 1626387-80-1

サイズ 価格 在庫数 個数
10mM (in 1mL DMSO)
$48.00
在庫あり
5 mg
$42.00
在庫あり
10 mg
$54.00
在庫あり
50 mg
$108.00
在庫あり
100 mg
$171.00
在庫あり

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment:

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. The detailed protocols could be obtained from Millipore. In brief, recombinant kinases are incubated within 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 filtermat 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].

Cell experiment:

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 0.3μM 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].

Animal experiment:

Rats[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.

References:

[1]. Zeng Q, et al. Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. J Med Chem. 2015 Oct 22;58(20):8200-15.

Background

AZD3759 is a potent and oral active inhibitor of EGFR (IC50= 7.0-7.7 nM) with antineoplastic activity.

EGFR (epidermal growth factor receptor) is a cell-surface receptor tyrosine kinase. The receptor activation leads to dimerization and tyrosine autophosphorylation. It induces a cascade of downstream cellular responses such as modification in gene expression, cell proliferation and cytoskeletal rearrangement etc.

AZD3759 shows equally potent inhibitory effect on cell phosphorylation or proliferation in EGFR-activating mutant cell lines (PC-9 and H3255) in the range of 7.0−7.7nM. In cellular phosphorylation assays, AZD3759 also exhibits 9-fold inhibition selectivity in EGFR-activating

mutant cell lines over EGFR wild-type cell lines (H838). [1]

In brain metastasis mouse model, AZD3759 demonstrates prominent antitumor efficacy in a dose dependent manner (∼78% tumor growth inhibition at 7.5 mg/kg qd and tumor regression at 15 mg/kg qd, respectively, 4 weeks after treatment, with <20% body weight loss). In addition, at the doses of 7.5 and 15 mg/k, AZD3759 significantly decreases tumor area in the brain tissue collected from the same mouse model. [1]

Reference:
Zeng Q, Wang J, Cheng Z et al.  Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. J Med Chem. 2015 Oct 22;58(20):8200-15

Chemical Properties

Cas No. 1626387-80-1 SDF
同義語 AZD3759
Chemical Name (R)-4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl 2,4-dimethylpiperazine-1-carboxylate
Canonical SMILES ClC1=CC=CC(NC2=NC=NC3=CC(OC)=C(OC(N4[C@H](C)CN(C)CC4)=O)C=C23)=C1F
Formula C22H23ClFN5O3 M.Wt 459.9
溶解度 ≥ 23mg/mL in DMSO Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 2.1744 mL 10.8719 mL 21.7439 mL
5 mM 0.4349 mL 2.1744 mL 4.3488 mL
10 mM 0.2174 mL 1.0872 mL 2.1744 mL
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Average Rating: 5 ★★★★★ (Based on Reviews and 39 reference(s) in Google Scholar.)

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