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  • Dasatinib hydrochloride
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Dasatinib hydrochloride

An inhibitor of Abl and Src

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  • 货号: ajce55866
  • CAS: 854001-07-3
  • 别名: 达沙替尼盐酸盐; BMS-354825 hydrochloride
  • 分子式: C22H27Cl2N7O2S
  • 分子量: 524.47
  • 纯度: >98%
  • 溶解度: DMSO: 15 mg/mL (28.60 mM and warming); Water: 10 mg/mL (19.07 mM)
  • 储存: Store at 2-8°C,stored under nitrogen
  • 库存: 现货

Background

Dasatinib is a potent inhibitor of the non-receptor tyrosine kinases Abl and Src as well as other members of the Src family.1,2 It is effective at sub-nanomolar concentrations, inhibiting Src, Abl, and Lck with IC50 values of 0.05, 0.5, and 0.4 nM, respectively.1,3,4 At nanomolar concentrations, dasatinib also blocks the activity of several other receptor and non-receptor tyrosine kinases, plus drug resistant mutants.3,4 Because of these activities, dasatinib has potential therapeutic value in diseases that are characterized by elevated levels of these kinases, including some forms of cancer and fibrotic disease.1,5,6,7


1.Lombardo, L.J., Lee, F.Y., Chen, P., et al.Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825),a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assaysJ. Med. Chem.47(27)6658-6661(2004) 2.Das, J., Chen, P., Norris, D., et al.2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitorJ. Med. Chem.49(23)6819-6823(2006) 3.Davis, M.I., Hunt, J.P., Herrgard, S., et al.Comprehensive analysis of kinase inhibitor selectivityNat. Biotechnol.29(11)1046-1051(2011) 4.Carter, T.A., Wodicka, L.M., Shah, N.P., et al.Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinasesProc. Natl. Acad. Sci. USA102(31)11011-11016(2005) 5.El-Amm, J., Freeman, A., Patel, N., et al.Bone-targeted therapies in metastatic castration-resistant prostate cancer: Evolving paradigmsProstate Cancer20131-10(2013) 6.Distler, J.H.W., and Distler, O.Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosisRheumatology47(Suppl 5)10-11(2008) 7.McFarland, K.L., and Wetzstein, G.A.Chronic myeloid leukemia therapy: Focus on second-generation tyrosine kinase inhibitorsCancer Control16(2)132-140(2009)

Protocol

Cell experiment:

Ba/F3 cell lines are plated in triplicate and incubated with escalating concentrations of STI571, AMN107, or Dasatinib for 72 hours. Proliferation is measured using a methanethiosulfonate-based viability assay (CellTiter96 Aqueous One Solution Reagent). IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges for IC50 and IC90determinations are 0 to 2,000 nM (STI571 and AMN107) or 0 to 32 nM (Dasatinib). The STI571 concentration range is extended to 6,400 nM for mutants with IC50>2,000 nM. The Dasatinib concentration range is extended to 200 nM for mutant T315I.

Animal experiment:

Mice[3]Male athymic nude mice (25 grams; 5-week old) are used. Dasatinib (50 mg/kg) is prepared for daily oral gavage (5 d/wk) in 80 mM sodium citrate buffer, pH 3.0. For the orthotopic murine model, mice are randomized on day 10 based on bioluminescence activity to receive drug or vehicle. In the metastatic murine model, mice receives dasatinib or vehicle, as described earlier, starting 2 days before intracardiac injection (pretreatment), or on day 11 following randomization (posttreatment).Rats[4]Dasatinib is dosed to male Wistar-Han (WH) rats at 50 mg/kg orally in 0.5% methylcellulose. The automated rat blood collection device is programmed to collect 200 μL of blood at predetermined intervals. At each time point, the accusampler is programmed to directly spot 20 μL of blood twice (two spots) onto the DBS card. The remaining 160 μL of liquid blood is collected into sodium EDTA-containing tubes. Plasma samples are obtained after immediate centrifugation of blood at 11,000 rpm for 5 min. The plasma samples are stored at ?80°C until analyses. The DBS samples are dried under room temperature for a minimum of 2 h and stored in a plastic bag in the dessicator until sample analysis.

参考文献:

[1]. O'Hare T, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant STI571-resistant Abl kinase domain mutants. Cancer Res. 2005 Jun 1;65(11):4500-5.
[2]. Shah NP, et al. Dasatinib (BMS-354825) inhibits KITD816V, an STI571-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood. 2006 Jul 1;108(1):286-91.
[3]. Chan CM, et al. Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis. Clin Cancer Res. 2012 Jul 1;18(13):3580-91.
[4]. Shen Z, et al. Metabolite profiling of dasatinib dosed to Wistar Han rats using automated dried blood spot collection. J Pharm Biomed Anal. 2012 Aug-Sep;67-68:92-7.

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