Metabolite of Dasatinib; Src/Bcr-Abl

一些癌症细胞发生染色体易位，导致慢性粒细胞白血病（CML）中包括BCR-ABL在内的异常致癌融合蛋白的表达。ABL酪氨酸激酶抑制剂，如伊马替尼和达沙替尼，显示出显著的治疗效果，尽管在长期治疗期间出现耐药性阻碍了治疗。治疗慢性粒细胞白血病的另一种方法是下调BCR-ABL蛋白。我们设计了一种名为凋亡蛋白特异性和非遗传抑制剂[IAP]依赖性蛋白清除器（SNIPR）的杂交分子的蛋白质敲除系统，旨在诱导IAP介导的靶蛋白泛素化和蛋白酶体降解，最近开发了一对针对BCR-ABL蛋白的SNIPR（ABL）。在这项研究中，我们测试了ABL抑制剂和IAP配体的各种组合，并针对SNIPER（ABL）的蛋白质敲除活性对接头进行了优化。由此产生的SNIPR（ABL）-39，其中达沙替尼通过聚乙二醇（PEG）×3接头与IAP配体LCL161衍生物偶联，显示出降解BCR-ABL蛋白的强大活性。机制分析表明，细胞凋亡抑制蛋白1（cIAP1）和X连锁凋亡抑制蛋白（XIAP）都在BCR-ABL蛋白的降解中发挥作用。与BCR-ABL蛋白的降解一致，SNIPER（ABL）-39抑制了信号转导子和转录激活子5（STAT5）和Crk样原癌基因（CrkL）的磷酸化，并抑制了BCR-ABL阳性CML细胞的生长。这些结果表明，SNIPER（ABL）-39可能是一种针对BCR-ABL阳性CML的基于降解的新型抗癌药物的候选者[1]。

1.19 N-去羟乙基达沙替尼在Wistar大鼠体内的药代动力学特征[2]。 N-去羟乙基达沙替尼 2.05 8.7 23.9 2.0 10.293 0.072 分析物 Cmax (ng/mL) AUC0-t (h*ng/mL) AUC0-inf (h*ng/mL) Tmax (h) T1/2 (h) Kel (h -1)

Dasatinib is a multi-kinase inhibitor that potently inhibits Bcr-Abl, Src family and platelet-derived growth factor receptor kinases. Methotrexate is an antimetabolite and antifolate drug. Clinical trials utilizing a combination of dasatinib and methotrexate in patients with Philadelphia chromosome positive and/or Bcr-Abl positive acute lymphoblastic leukemia are currently ongoing. A need therefore exists to develop a sensitive analytical method for determination of dasatinib and methotrexate in plasma.To estimate methotrexate, dasatinib and its active metabolite N-deshydroxyethyl dasatinib simultaneously using liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) in Wistar rat plasma.The analytes were extracted by using liquid-liquid extraction procedure and separated on a reverse phase C18 column (50 mm×3 mm i.d., 4.6 µ) using methanol: 2 mM ammonium acetate buffer, pH 4.0 as mobile phase at a flow rate 1 mL/min in gradient mode. Selective reaction monitoring was performed using the transitions m/z 455.0>175.0, 488.1 > 401.0, 444.26>401.0, and 271.1>- 155.0 to quantify methotrexate, dasatinib, N-deshydroxyethyl dasatinib and tolbutamide respectively.The method was validated over the concentration range of 1-1 000 ng/mL and the lower limit of quantitation was 1 ng/mL. The recoveries from spiked control samples were > 79% for all analytes and internal standard Intra- and Interday accuracy and precision of validated method were within the acceptable limits of < 15% at all concentration.The quantitation method was successfully applied for simultaneous estimation of methotrexate, dasatinib and N- deshydroxyethyl dasatinib in a pharmacokinetic study in Wistar rats.[2]

[1]. Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands. Cancer Sci. 2017 Aug;108(8):1657-1666.

[2]. Simultaneous determination of methotrexate, dasatinib and its active metabolite N- deshydroxyethyl dasatinib in rat plasma by LC-MS/MS: method validation and application to pharmacokinetic study. Arzneimittelforschung. 2012 Dec;62(12):624-30.

C20H22CLN7OS

443.95300

443.13

910297-51-7

N-Deshydroxyethyl Dasatinib-d8;1189998-96-6; Dasatinib N-oxide-d8;1189988-36-0; Dasatinib hydrochloride;854001-07-3;Dasatinib monohydrate;863127-77-9;Dasatinib-d8;1132093-70-9; 302962-49-8 (free); 2112837-79-1 (cabaldehyde); 910297-52-8 (N-oxide)

11669430

White to off-white solid powder

1.404g/cm3

>300ºC

1.69

4.148

123.31

3

8

5

30

581

0

DOBZFFWLHXORTB-UHFFFAOYSA-N

InChI=1S/C20H22ClN7OS/c1-12-4-3-5-14(21)18(12)27-19(29)15-11-23-20(30-15)26-16-10-17(25-13(2)24-16)28-8-6-22-7-9-28/h3-5,10-11,22H,6-9H2,1-2H3,(H,27,29)(H,23,24,25,26)

N-(2-chloro-6-methylphenyl)-2-[(2-methyl-6-piperazin-1-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide

N-Deshydroxyethyl Dasatinib; 910297-51-7; BMS-528691; N-Deshydroxyethyl dasatinib metabolite M4; UNII-38T0L9673E; 38T0L9673E; N-(2-chloro-6-methylphenyl)-2-[(2-methyl-6-piperazin-1-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide; N-(2-chloro-6-methylphenyl)-2-[[2-methyl-6-(1-piperazinyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~55 mg/mL (~123.89 mM)

配方 1 中的溶解度: ≥ 2.75 mg/mL (6.19 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 27.5 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.75 mg/mL (6.19 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.75 mg/mL (6.19 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。