| 名稱 | Dasatinib monohydrate |
| 描述 | Dasatinib monohydrate (BMS-354825 Monohydrate) is an orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib monohydrate binds to and inhibits the growth-promoting activities of these kinases. Apparently, because of its less stringent binding affinity for the BCR-ABL kinase, Dasatinib monohydrate has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. |
| 細(xì)胞實(shí)驗(yàn) | Ba/F3 cell lines are seeded in triplicate and incubated with escalating concentrations of Dasatinib for 72 hours. Proliferation is 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 are 0 nM to 32 nM (Dasatinib). The Dasatinib concentration range is extended to 200 nM for mutant T315I.(Only for Reference) |
| 激酶實(shí)驗(yàn) | Kinase autophosphorylation assays: Kinase assays using wild-type and mutant glutathione S-transferase (GST)-Abl fusion proteins (c-Abl amino acids 220-498) are done. GST-Abl fusion proteins are released from glutathione-Sepharose beads before use; the concentration of ATP is 5 μM. Immediately before use in kinase autophosphorylation and in vitro peptide substrate phosphorylation assays, GST-Abl kinase domain fusion proteins are treated with LAR tyrosine phosphatase. After 1-hour incubation at 30 °C, LAR phosphatase is inactivated by addition of sodium vanadate (1 mM). Immunoblot analysis comparing untreated GST-Abl kinase to dephosphorylated GST-Abl kinase is routinely done using phosphotyrosine-specific antibody 4 g10 to confirm complete (>95%) dephosphorylation of tyrosine residues and c-Abl antibody CST 2862 to confirm equal loading of GST-Abl kinase. The Dasatinib concentration range is extended to 1,000 nM for mutant T315I. These same inhibitor concentrations are used for the in vitro peptide substrate phosphorylation assays. The three inhibitors are tested over these same concentration ranges against GST-Src kinase and GST-Lyn kinase. |
| 體外活性 | 在TgE小鼠體內(nèi),Dasatinib特異性抑制骨髓B細(xì)胞（LMP2A表達(dá)）形成集落,并使脾臟大小減少.與對(duì)照組Tg6/λ-MYC小鼠相比,Dasatinib處理組脾臟腫塊顯著變小.Dasatinib對(duì)MYC/LMP2A雙重轉(zhuǎn)基因小鼠體內(nèi)的淋巴結(jié)腫大具有抑制作用,并可逆轉(zhuǎn)脾腫大.從LMP2A/MYC雙重轉(zhuǎn)基因小鼠移植腫瘤細(xì)胞至Rag1KO小鼠,Dasatinib可逆轉(zhuǎn)該脾腫大.Dasatinib可抑制B淋巴腫瘤細(xì)胞（表達(dá)LMP2A）中Lyn磷酸化. |
| 體內(nèi)活性 | Dasatinib對(duì)野生型Abl激酶及其所有突變體（除T315I外）具有有效的抑制作用。Dasatinib直接靶向所有突變型Abl激酶域,濃度依賴性地抑制底物和自身磷酸化。與伊馬替尼相比,Dasatinib對(duì)表達(dá)Bcr-Abl（野生型和除T315I外的突變型）的Ba/F3細(xì)胞增殖具有更有效的抑制作用。與伊馬替尼相比,Dasatinib對(duì)表達(dá)野生型Bcr-Abl的細(xì)胞表現(xiàn)出325倍的效能。在Dasatinib處理后TgE骨髓細(xì)胞集落百分?jǐn)?shù)從100%降為4.12%。在Dasatinib存在下,WT和TgE骨髓細(xì)胞形成的集落百分比具有明顯的統(tǒng)計(jì)學(xué)差異。Dasatinib抑制LMP2A表達(dá)引起的B淋巴細(xì)胞存活和增殖。 Dasatinib可抑制部分甲狀腺癌細(xì)胞的Src信號(hào),抑制細(xì)胞生長(zhǎng),并誘導(dǎo)細(xì)胞凋亡和細(xì)胞周期阻滯。以Dasatinib（0.019 μM~1.25 μM）治療3天,抑制大約50%的BCPAP,C643,SW1736和TPC1細(xì)胞系生長(zhǎng),但需要更高的濃度才能抑制K1細(xì)胞系生長(zhǎng)。在BCPAP,SW1736和K1細(xì)胞中,Dasatinib（10 nM或50 nM）可使G1期細(xì)胞增加9-22%,而S期細(xì)胞相應(yīng)減少7-18%。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : < 1 mg/mL (insoluble or slightly soluble)
H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 55 mg/mL (108.69 mM)
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| 關(guān)鍵字 | orally | Bcr-Abl | Dasatinib | Apoptosis | Dasatinib monohydrate | prostate | inhibit | Autophagy | CML | BMS 354825 Monohydrate | K562 | Inhibitor | BMS-354825 | colon | antiproliferative | PC3 | WiDr | BMS354825 Monohydrate | Src | breast | Dasatinib Monohydrate | BMS 354825 | active | antitumor | BMS354825 |
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