A-385358
目录号 : GC32981
A-385358是Bcl-XL的一个选择性抑制剂，对于Bcl-XL和Bcl-2的Ki值分别为0.80和67nM。
Cas No.:406228-55-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | FL5.12 cells suspended in EMB growth medium containing 4% fetal bovine serum (FBS) are incubated at 37°C for 1 hour in 10 μM A-385358. Compound concentration is determined by high-performance liquid chromatography before and after the 1-hour incubation following brief centrifugation. To analyze membrane-bound fractions following compound incubation, cells are washed once with 10 volumes of cold PBS and lysed with 4 mL of water. A-385358 concentration is determined from aliquots of lysate before and after centrifugation[1]. |
Cell experiment: | A549 cells (1×105) are plated in 96-well plates in medium containing 10% fetal bovine serum. Following attachment, A-385358 is added to one set of wells (final concentration of 50 μM in 10% FBS) and medium is added to another set. [3H]Paclitaxel (5 μM; 0.5 μCi/mL final concentration) is added to all wells and the cells are incubated at 37°C for various periods of time. For washout experiments, cells are exposed first to [3H]paclitaxel for 2 hours. The cells are washed once with medium and then incubated with fresh medium with or without 50 μM A-385358 at 37°C for various periods of time[1]. |
Animal experiment: | For efficacy studies, male CD-1 nude mice are inoculated with a 1:5 dilution of tumor brei in 50% Matrigel and analysis is conducted. A-385358 is delivered in a vehicle containing 5% Tween 80, 20% propylene glycol, and 75% PBS (pH 3.8). Paclitaxel is formulated according to the recommendations of the manufacturer. For combination therapy of paclitaxel plus A-385358, both drugs are administered i.p. with the paclitaxel given several hours before treatment with A-385358 (except for immunohistochemistry studies looking at expression of MPM-2 and caspase-3 wherein the two drugs are given simultaneously)[1]. |
References: [1]. Shoemaker AR, et al. A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo. Cancer Res. 2006 Sep 1;66(17):8731-9. | |
A-385358 is a selective inhibitor of Bcl-XL with Kis of 0.80 and 67 nM for Bcl-XL and Bcl-2, respectively.
A-385358 is a selective inhibitor of Bcl-XL with Kis of 0.80 and 67 nM for Bcl-XL and Bcl-2, respectively, in fluorescence polarization assays. Treatment of IL-3-deprived FL5.12/Bcl-XL cells for 24 hours with A-385358 results in cell killing with an EC50 of 0.47±0.05 μM (n=68). This effect is accompanied by an increase in caspase-3 activity. Consistent with the greater affinity for the Bcl-XL versus Bcl-2 hydrophobic grooves, the EC50 of A-385358 for IL-3-depleted FL5.12/Bcl-2 cells (1.9±0.1 μM; n=55) is 4-fold higher relative to the cytokine-deprived FL5.12/Bcl-XL cells. In addition, A-385358 is more effective at stimulating cytochrome c release from mitochondria isolated from FL5.12/Bcl-XL versus Bcl-2 cells[1].
The combination of A-385358 given at 100 mg/kg/d plus the lower dose of paclitaxel produces a significant reduction in tumor growth (%T/C) compare with paclitaxel monotherapy. This combination also yields a >100% increase in time for tumors to reach 900 mm3 (%ILS) compare with vehicle control. Maximal efficacy is observed during the dosing period for A-385358, with slow but steady increase in the tumor growth after termination of treatment. The combination of A-385358 at 75 mg/kg/d plus paclitaxel at 30 mg/kg/d is also well tolerated and inhibits tumor growth rate by nearly 80%. Significant effects on tumor growth relative to paclitaxel monotherapy are observed with doses as low as 50 mg/kg/d[1].
[1]. Shoemaker AR, et al. A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo. Cancer Res. 2006 Sep 1;66(17):8731-9.
| Cas No. | 406228-55-5 | SDF | |
| Canonical SMILES | O=C(NS(=O)(C1=CC=C(N[C@@H](CSC2=CC=CC=C2)CCN(C)C)C([N+]([O-])=O)=C1)=O)C3=CC=C(N4CCC(C)(C)CC4)C=C3 | ||
| 分子式 | C32H41N5O5S2 | 分子量 | 639.83 |
| 溶解度 | DMSO : 125 mg/mL (195.36 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.5629 mL | 7.8146 mL | 15.6292 mL |
| 5 mM | 0.3126 mL | 1.5629 mL | 3.1258 mL |
| 10 mM | 0.1563 mL | 0.7815 mL | 1.5629 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo
Cancer Res 2006 Sep 1;66(17):8731-9.PMID:16951189DOI:10.1158/0008-5472.CAN-06-0367.
Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.