| 名稱 | Dasatinib |
| 描述 | Dasatinib (BMS-354825) is a tyrosine kinase inhibitor that inhibits Src and Bcr-Abl (Ki=16/30 pM) and is orally active and ATP-competitive. Dasatinib has antitumor activity and is used in the treatment of leukemia and lymphoma. |
| 細(xì)胞實(shí)驗(yàn) | Ba/F3 cell lines were plated in triplicate and incubated with escalating concentrations of imatinib, AMN107, or BMS-354825 for 72 hours. Proliferation was measured using a methanethiosulfonate-based viability assay. IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges for IC50 and IC90 determinations were 0 to 2,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The imatinib concentration range was extended to 6,400 nmol/L for mutants with IC50 >2,000 nmol/L. The BMS-354825 concentration range was extended to 200 nmol/L for mutant T315I [1]. |
| 激酶實(shí)驗(yàn) | Kinase assays using wild-type and mutant glutathione S-transferase (GST)–Abl fusion proteins (c-Abl amino acids 220-498) were done as described, with minor alterations. GST-Abl fusion proteins were released from glutathione-Sepharose beads before use; the concentration of ATP was 5 μmol/L. Immediately before use in kinase autophosphorylation and in vitro peptide substrate phosphorylation assays, GST-Abl kinase domain fusion proteins were treated with LAR tyrosine phosphatase according to the manufacturer's instructions. After 1-hour incubation at 30°C, LAR phosphatase was inactivated by addition of sodium vanadate (1 mmol/L). Immunoblot analysis comparing untreated GST-Abl kinase to dephosphorylated GST-Abl kinase was routinely done using phosphotyrosine-specific antibody 4G10 to confirm complete (>95%) dephosphorylation of tyrosine residues and c-Abl antibody CST 2862 to confirm equal loading of GST-Abl kinase. The inhibitor concentration ranges for IC50 determinations were 0 to 5,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The BMS-354825 concentration range was extended to 1,000 nmol/L for mutant T315I. These same inhibitor concentrations were used for the in vitro peptide substrate phosphorylation assays. The three inhibitors were tested over these same concentration ranges against GST-Src kinase and GST-Lyn kinase [1]. |
| 動物實(shí)驗(yàn) | For in vivo studies, dasatinib (50 mg/kg) was prepared for daily oral gavage (5 d/wk) in 80 mmol/L sodium citrate buffer, pH 3.0. For the orthotopic murine model, mice were randomized on day 10 based on bioluminescence activity to receive drug or vehicle. In the metastatic murine model, mice received dasatinib or vehicle, as described earlier, starting 2 days before intracardiac injection (pretreatment), or on day 11 following randomization (posttreatment) [4]. |
| 體外活性 | 方法：8 種甲狀腺癌細(xì)胞用 Dasatinib (0.019-1.25 μmol/L) 處理 3 天，使用 SRB 方法檢測細(xì)胞增殖。
結(jié)果：Dasatinib 對 C643、TPC1、BCPAP、SW1736、K1、8505C、HTh74、HTh7 細(xì)胞的 IC50 分別為 0.09、0.03、0.04、0.08、0.4、2.7、>5、1.6 μmol/L。[1]
方法：人肺癌細(xì)胞 NCI-H1975 和 NCI-H1650 用 Dasatinib (2.5-20 μM) 處理 48 h，使用 Flow Cytometry 檢測細(xì)胞凋亡情況。
結(jié)果：Dasatinib 在 10 和 20 μM 下誘導(dǎo) NCI-H1975 和 NCI-H1650 細(xì)胞凋亡。[2] |
| 體內(nèi)活性 | 方法：為檢測體內(nèi)抗腫瘤活性，將 Dasatinib (50 mg/kg in 80 mmol/L sodium citrate buffer, pH 3.0) 口服給藥給攜帶人甲狀腺癌腫瘤 BCPAP 或 8505C 的 athymic nude 小鼠，每周五天，持續(xù)二十天。
結(jié)果：Dasatinib 顯著抑制 BCPAP 原位腫瘤，最終腫瘤體積抑制了 90% 以上。Dasatinib 治療在任何時間點(diǎn)都沒有顯著抑制 8505C 來源的腫瘤的生長。[1]
方法：為研究對神經(jīng)炎癥的影響，將 Dasatinib (20 mg/kg in 4%DMSO+30%PEG+5%Tween 80) 腹腔注射或口服給藥給 C57BL6/N 小鼠，每天一次給藥四天，隨后腹腔注射 LPS (10? mg/kg) 誘導(dǎo)體內(nèi)神經(jīng)炎癥反應(yīng)。
結(jié)果：腹腔注射和口服 Dasatinib 抑制 LPS 誘導(dǎo)的野生型小鼠腦中小膠質(zhì)細(xì)胞/星形膠質(zhì)細(xì)胞活化、促炎細(xì)胞因子水平和中性粒細(xì)胞滾動。[3] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 9.1 mg/mL (18.65 mM), Suspension. Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
DMSO : 55 mg/mL (112.7 mM)
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| 關(guān)鍵字 | active | antiproliferative | CML | antitumor | breast | Inhibitor | prostate | Bcr-Abl | Autophagy | BMS354825 | Apoptosis | colon | K562 | WiDr | PC3 | orally | BMS 354825 | inhibit | Dasatinib | Src |
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