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KU-0060648

现货
Catalog No.
A1769
DNA-PK/PI3-K双重抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 1,500.00
Ship with 10-15 days
25mg
¥ 6,000.00
Ship with 10-15 days
100mg
¥ 15,000.00
Ship with 10-15 days

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Background

IC50: KU-0060648 inhibited cellular DNA-PK autophosphorylation with IC50 values of 0.17 μmol/L (SW620 cells) and 0.019 μmol/L (MCF7 cells), and PI-3K–mediated AKT phosphorylation with IC50 values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells).
DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs), which promotes cell survival and proliferation and is upregulated in many cancers, is structurally similar to PI-3K,. KU-0060648 is a dual inhibitor of DNA-PKand PI-3K in vitro.
In vitro: KU-0060648 was investigated in a panel ofhumanbreast and colon cancer cells. Five-day exposure to 1 μM KU-0060648 was found to inhibite cell proliferation by more than 95% in MCF7 cells but only by 55% in SW620 cells. KU-0060648 increased the etoposide and doxorubicin cytotoxicity across the DNA-PKcs–proficient cell panel rather than in DNA-PKcs–deficient cells, therefore confirming the enhanced cytotoxicity was due to the inhibition of DNA-PK [1].
In vivo: In mice bearing SW620 and MCF7 xenografts, KU-0060648 concentrations that were sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor at nontoxic doses for at least 4 hours. KU-0060648 alone delayed the MCF7 xenografts growth and increased etoposide-induced tumor growth delay in both in MCF7 and SW620 xenografts by up to 4.5 folds, without causing etoposide toxicity to unacceptable levels [1].
Clinical trial: KU-0060648 is still in pre-clinical development stage and no clinicl trial is ongoing currently.
Reference:
[1] Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear K, Slade A, Thommes P, Martin NM, Newell DR, Smith GC, Curtin NJ. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012;11(8):1789-98.

文献引用

1. Boel A, De Saffel H, et al. "CRISPR/Cas9-mediated homology-directed repair by ssODNs in zebrafish induces complex mutational patterns resulting from genomic integration of repair-template fragments." Dis Model Mech. 2018 Oct 18;11(10). pii: dmm035352. PMID:30355591

Chemical Properties

StorageStore at -20°C
M.Wt582.71
Cas No.881375-00-4
FormulaC33H34N4O4S
SolubilityLimited solubility, soluble in HCl
Chemical Name2-(4-ethylpiperazin-1-yl)-N-[4-(2-morpholin-4-yl-4-oxochromen-8-yl)dibenzothiophen-1-yl]acetamide
SDFDownload SDF
Canonical SMILESCCN1CCN(CC1)CC(=O)NC2=C3C4=CC=CC=C4SC3=C(C=C2)C5=CC=CC6=C5OC(=CC6=O)N7CCOCC7
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

细胞实验 [1]:

细胞系

人类乳腺癌细胞(MCF7、T47D和MDA-MB-231)和结肠癌细胞(LoVo和SW620)

制备方法

在DMSO中的溶解度受限。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C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 °C可放置数月。

反应条件

1 μM;5天

实验结果

持续暴露于1 μM KU-0060648(5天)抑制所有癌细胞生长(超过50%)。KU-0060648对LoVo和MCF7细胞的生长抑制作用最大。经KU-0060648处理的LoVo和MCF7细胞的总细胞生长仅为对照组的10%和4%。

动物实验 [1]:

动物模型

携带MCF7异种移植物的小鼠

给药剂量

10 mg/kg;腹腔注射;每天2次

实验结果

在携带MCF7异种移植物的小鼠中,单独给予KU-0060648导致的中值生长延迟为30天,其毒性可忽略。KU-0060648和Etoposide Phosphate联合用药导致中值生长延迟为55天,伴有可接受的毒性。

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]. Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear K, Slade A, Thommes P, Martin NM, Newell DR, Smith GC, Curtin NJ. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012;11(8):1789-98.

生物活性

Description KU-0060648是一种ATP竞争性的DNA依赖性蛋白激酶(DNA-PK)和PI3-K双重抑制剂,对DNA-PK、PI3-Kδ、PI3-Kβ和PI3-Kα的IC50值分别为19 nM、小于0.1 nM、0.5nM和4 nM。
靶点 DNA-PK PI3-Kδ PI3-Kβ PI3-Kα    
IC50 19 nM <0.1 nM 0.5nM 4 nM    

质量控制

质量控制和MSDS

批次:

化学结构

KU-0060648

相关生物数据

KU-0060648