| 名稱 | AZD-1480 |
| 描述 | AZD1480 is a novel ATP-competitive JAK2 inhibitor (IC50: 0.26 nM), selectivity act against Tyk2 and JAK3, and to a smaller extent against JAK1. AZD1480 has been used in trials studying the treatment of Solid Malignancies, Post-Polycythaemia Vera, Primary Myelofibrosis (PMF), and Essential Thrombocythaemia Myelofibrosis. |
| 細胞實驗 | Renca or 786-O cells are suspended in DMEM medium with 5% FBS , and seeded in 96-well plates (5×103 per well) to allow adhesion and then treated with DMSO or AZD1480 for 48 hours. Cell viability is determined by MTS assay. Absorbance at 490 nm is measured with Mikrotek Laborsysteme. Mouse endothelial cells and splenic CD11b+/c- myeloid cells are enriched from tumor-bearing mice,and cultured in 5% FBS RPMI-1640 medium. HUVECs are cultured on collagen 1–coated plates in complete medium. All cells are treated with DMSO and AZD1480 at various doses for 24 hours. Cell viability is determined by counting cell number manually. All the experiments are repeated 3 times. (Only for Reference) |
| 激酶實驗 | kinase assays: Inhibition studies of AZD1480 are performed using recombinant Jak1, Jak2, or Jak3 under buffer conditions of 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween-20, 50 mM/ml BSA, and 10 mM MgCl2. Jak3 enzyme is expressed as N-terminal GST fusion in insect cells and purified by glutathione-affinity and size-exclusion chromatographies. Enzymes are assayed in the presence of AZD1480 (10 point dose response, in triplicate, from 8.3 μM to 0.3 nM in half-log dilution steps) using 1.5 μM peptide substrate (Jak1: FITC-C6-KKHTDDGYMPMSPGVA-NH2, Jak2 and Jak3: FAM-SRCtide) and screened under their respective ATP Km (Jak1: 55 μM, Jak2: 15 μM, Jak3: 3 μM) and approximated physiological ATP concentration of 5 mM. Phosphorylated and unphosphorylated peptides are separated and quantified by a Caliper LC3000 system for calculating percent inhibition. |
| 體外活性 | AZD1480抑制皮下移植瘤的生長,并通過對STAT3活性的抑制使攜帶顱內(nèi)惡性膠質(zhì)瘤的鼠壽命延長,表明AZD1480對JAK/STAT3通路的抑制作用可用于研究治療攜帶顱內(nèi)惡性膠質(zhì)瘤的患者.AZD1480可抑制人類實體瘤模型和多發(fā)性骨髓瘤模型的STAT3磷酸化.AZD1480可降低人類移植瘤模型的血管生成和代謝.AZD1480對含STAT活性的人類實體瘤的生長有抑制作用.AZD1480對骨髓細胞的肺轉(zhuǎn)移和肺浸潤瘤也有抑制作用. |
| 體內(nèi)活性 | 通過影響腫瘤的微環(huán)境,AZD1480可抑制腫瘤局部轉(zhuǎn)移和血管生成。作為JAK2的有效抑制劑,AZD1480可抑制人類多發(fā)性骨髓瘤細胞的生長和存活,并抑制FGFR3和STAT3信號及下游靶點,包括Cyclin D2。低微摩爾濃度AZD1480可誘導骨髓瘤細胞系凋亡和抑制細胞增殖。 AZD1480（5 μM）誘導細胞周期停在G2/M期,并通過抑制Aurora激酶而誘導細胞死亡。在人和鼠神經(jīng)膠質(zhì)瘤細胞中,AZD1480有效抑制組成型和誘導型JAK1/2及STAT-3的磷酸化作用 ,從而降低細胞增殖并誘導凋亡。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | 10% DMSO+90% Saline : < 7.25 mg/mL (20.79 mM), Lower concentrations may be soluble, but exact solubility limit is unknown.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 72.5 mg/mL (207.87 mM), Sonication is recommended.
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 7.25 mg/mL (20.79 mM), Solution.
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| 關(guān)鍵字 | Janus kinase | JAK2 | JAK | Inhibitor | inhibit | AZD-1480 | AZD1480 | AZD 1480 |
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| 相關(guān)庫 | 抑制劑庫 | 經(jīng)典已知活性庫 | 抗癌活性化合物庫 | 已知活性化合物庫 | 激酶抑制劑庫 | 臨床失敗化合物庫 | 抗衰老化合物庫 | 膜蛋白靶向化合物庫 | 免疫/炎癥分子化合物庫 | 酪氨酸激酶分子庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |