| 名稱 | AZD8330 |
| 描述 | AZD8330 (ARRY-704) is a novel, selective, non-ATP competitive MEK 1/2 inhibitor with IC50 of 7 nM. Phase 1. |
| 細(xì)胞實(shí)驗(yàn) | Malme-3M melanoma cells are plated in 96-wells and treated with various concentrations of AZD8330 for 1 hour at 37 °C. The cells are fixed, permeabilized, and incubated with an anti-phospho-ERK antibody and an anti-ERK 1/2 antibody. Plates are washed and fluorescently-labeled secondary antibodies are added. Plates are analyzed on a LICOR fluorescence imager. The pERK signal is normalized to the total ERK signa (Only for Reference) |
| 激酶實(shí)驗(yàn) | MEK1 enzymatic assays: NH2-terminal hexahistidine tagged, constitutively active MEK1 (S218D, S222D ΔR4F) is expressed in baculovirus-infected Hi5 insect cells and purified by immobilized metal affinity chromatography, ion exchange, and gel filtration. The activity of MEK1 is assessed by measuring the incorporation of [γ- 33P]phosphate from [γ-33P]ATP onto ERK2. The assay is carried out in a 96-well polypropylene plate with an incubation mixture (100 μL) composed of 25 mM HEPES (pH 7.4), 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM sodium orthovanadate, 5 mM DTT, 5 nM MEK1, 1 μM ERK2, and 0 to 80 nM AZD8330 (final concentration of 1% DMSO). The reactions are initiated by the addition of 10 μM ATP (with 0.5 μC k[γ-33P]ATP/well) and incubated at room temperature for 45 min. An equal volume of 25% trichloracetic acid is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filter plates, excess labeled ATP is washed off with 0.5% phosphoric acid, and radioactivity is counted in a liquid scintillation counter. ATP dependence is determined by varying the amount of ATP in the reaction mixture. The data are globally fitted. |
| 體外活性 | AZD8330 potently and strongly inhibits MEK 1/2. AZD8330 has no inhibitory activity against over 200 other kinases including at concentrations up to 10 μM. AZD8330 demonstrates sub-nanomolar potency in mechanistic (pERK) and low to sub-nanomolar potency in functional (proliferation) assays in MEK 1/2 inhibitor sensitive cell lines. [1] |
| 體內(nèi)活性 | In a Calu-6 rat xenograft pharmacokinetic/pharmacodynamic (PK/PD) model a single, 1.25 mg/kg oral dose of AZD8330 inhibits ERK phosphorylation by > 90% for between 4 and 8 hours. Doses as low as 0.4 mg/kg once daily are sufficient for > 80% tumor growth inhibition in the Calu-6 nude rat xenograft model. In the Calu-6 model, AZD8330 inhibits tumor growth in a dose-dependent fashion, at 0.3 mg/kg and 1.0 mg/kg once daily. [1] |
| 存儲(chǔ)條件 | Store at low temperature
Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : 85 mg/mL (184.29 mM), Sonication is recommended.
DMSO : 85 mg/mL (184.29 mM), Sonication is recommended.
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 2.5 mg/mL (5.42 mM), Sonication is recommended.
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| 關(guān)鍵字 | Mitogen-activated protein kinase kinase | MEK1/2 | MEK | MAPKK | MAP2K | Inhibitor | inhibit | ERK phosphorylation | AZD-8330 | AZD8330 | AZD 8330 | ARRY704 | ARRY424704 | ARRY 704 | ARRY 424704 |
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