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AP1903

现货
Catalog No.
B4168
FKBP配体的同型二聚体,与FKBP结合。
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 7,600.00
现货
5mg
¥ 3,320.00
现货
10mg
¥ 4,750.00
现货
50mg
¥ 14,250.00
现货
100mg
¥ 19,950.00
现货

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Background

IC50: 5 nM for F36V-FKBP in competition fluorescence polarization assay

FKBP ligand homodimers can be used to trigger signaling events inside cells and animals that have been engineered to express fusions between and FKBP appropriate signaling domains. However, use of these dimerizers in vivo is potentially limited by ligand binding to endogenous FKBP. AP1903 is a homodimer of the modified ligand for FKBP.

In vitro: By selective inhibition of FKBP, AP1903 elicited potent and dose-dependent apoptotic death of the human fibrosarcoma line HT1080 engineered cells in culture, with an EC50 of ~0.1 nM [1].

In vivo: In an mouse model of conditional cell ablation, animals were i.v. treated with various doses of AP1903, and then serum hGH levels were determined as a measure of the number of surviving cells. Results showed that AP1903 elicited a dose-dependent decrease in levels of serum hGH, with a half-maximal effective dose of 0.4 mg/kg [1].

Clinical trials: In an intravenous, single-blind, placebo- and saline-controlled, ascending-dose study, AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable PK profile at doses well above the anticipated therapeutic dose [2].

References:
[1] Clackson T, Yang W, Rozamus LW, Hatada M, Amara JF, Rollins CT, Stevenson LF, Magari SR, Wood SA, Courage NL, Lu X, Cerasoli F Jr, Gilman M, Holt DA.  Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42.
[2] Iuliucci JD, Oliver SD, Morley S, Ward C, Ward J, Dalgarno D, Clackson T, Berger HJ.   Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers. J Clin Pharmacol. 2001 Aug;41(8):870-9.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt1411.63
Cas No.195514-63-7
FormulaC78H98N4O20
Solubility≥23.5mg/mL in DMSO
SDFDownload SDF
Canonical SMILESO=C([C@@H](C(C=C1OC)=CC(OC)=C1OC)CC)N2[C@H](C(O[C@@H](C3=CC=CC(OCC(NCCNC(COC4=CC([C@H](CCC(C=C5OC)=CC=C5OC)OC([C@H]6N(C([C@@H](C(C=C7OC)=CC(OC)=C7OC)CC)=O)CCCC6)=O)=CC=C4)=O)=O)=C3)CCC(C=C8)=CC(OC)=C8OC)=O)CCCC2
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

FKBP结合实验

将亚饱和浓度的蛋白质与2.5 nM fluoro-FK506和竞争性配体的系列稀释物在Dynatech显微荧光板的孔中孵育30分钟。在Jolley FPM-2(Jolley Consulting and Research,Grayslake,IL)上读取偏振值。与不含竞争剂(100%)或不含蛋白质(0%)的对照相比,结合偏振的增加用作结合探针百分比的直接读数。通过使用四参数算法的非线性最小二乘法拟合确定导致50%探针置换(IC50)的竞争剂浓度。

细胞实验: [1]

细胞系

HT1080细胞系(ATCC CCL-121)

制备方法

溶解度有限,若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

37℃

实验结果

在稳定表达包含肉豆蔻酰化序列、两个拷贝的F36V-FKBP和人Fas胞内结构域的融合蛋白的人纤维肉瘤系HT1080中,AP1903以剂量依赖性方式有效诱导凋亡性细胞死亡,EC50约为0.1 nM。

动物实验: [1]

动物模型

雄性nu/nu小鼠

给药剂量

静脉注射,0.01-100 mg/kg

制备方法

以2 ml/kg配制在[50%N,N-二甲基乙酰胺/ 50%(90% PEG-400/10%吐温80)中

实验结果

向雄性nu/nu小鼠注射表达组成型分泌hGH的Fas-F36V-FKBP构建体的HT1080细胞系。AP1903以剂量依赖性方式降低血清hGH水平,半数最大有效剂量为0.4 ± 0.1 mg/kg。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

1. Clackson T, Yang W, Rozamus LW et al. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42

质量控制

化学结构

AP1903