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AG-14361

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Catalog No.
A4158
PARP1抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,540.00
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5mg
¥ 1,200.00
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10mg
¥ 2,300.00
现货
50mg
¥ 6,800.00
现货
100mg
¥ 9,900.00
现货

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Background

AG-14361 is a selective inhibitor of PARP-1 with Ki50 value

PARP1 is a member of PRAP family and plays an important role in many cellular processes, such as DNA repair, programmed cell death. It has been revealed that PARP1 is abnormally expressed in a variety of cancers and many PARP inhibitors have been developed as the anti-tumor drugs [1] [2] [3, 4].

AG-14361 is a potent PARP-1 inhibitor. When exposed HR and BRCA2-defective cells and parental cells to AG-14361, HR-defective cells were hypersensitive to the AG-14361 even at non-cytotoxic concentrations and lacking BRCA2 made the cells more sensitive to AG-14361 [5]. In human K562 cells, AG14361 treatment for 16 hours resulted in significant (~2-fold) potentiation of camptothecin-induced growth inhibition (GI50, 16 hours, camptothecin + AG14361 2.4 ± 0.1 nmol/L), cytotoxicity (LC50, camptothecin + AG14361 2.77 ± 0.55 nmol/L) and DNA single-strand breaks via inhibiting PARP-1 [1]. When tested with MMR-proficient (HCT-Ch3, A2780, and CP70-ch3) and MMR-deficient (HCT116, CP70, and CP70-ch2) cells, MMR-proficient cells were more sensitivity to temozolomide compared with MMR-deficient cells after exposed to AG-14361 which inhibited PARP1 activity [2].

In mouse model xenografted with BRCA2-deficient and BRCA-2 proficient tumor cells, BRCA2 deficiency group had more response even completely regressed tumor compared with BRCA-2 proficient group when treated with AG-14361 [5].

References:
[1].  Smith, L.M., et al., The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin Cancer Res, 2005. 11(23): p. 8449-57.
[2].  Curtin, N.J., et al., Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res, 2004. 10(3): p. 881-9.
[3].  Calabrese, C.R., et al., Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst, 2004. 96(1): p. 56-67.
[4].  Veuger, S.J., et al., Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res, 2003. 63(18): p. 6008-15.
[5].  Kyle, S., et al., Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer. Br J Radiol, 2008. 81 Spec No 1: p. S6-11.

文献引用

1. Soni H, Kaminski D, et al. "Cisplatin-induced oxidative stress stimulates renal Fas ligand shedding." Ren Fail. 2018 Nov;40(1):314-322. PMID:29619879

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt320.39
Cas No.328543-09-5
FormulaC19H20N4O
Solubility≥16 mg/mL in DMSO, ≥10.14 mg/mL in EtOH with ultrasonic and warming, <2.39 mg/mL in H2O
Chemical Name1-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one
SDFDownload SDF
Canonical SMILESO=C1N([H])C([H])([H])C([H])([H])N2C3=C1C([H])=C([H])C([H])=C3N=C2C(C([H])=C4[H])=C([H])C([H])=C4C([H])([H])N(C([H])([H])[H])C([H])([H])[H]
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

A549、LoVo和SW620细胞

溶解方法

在DMSO中的溶解度大于16 mg/mL。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

0.4 μM,5 d

应用

浓度为0.4 μM的AG14361可以抑制85%的PARP-1活性,但是对癌细胞的基因表达和生长没有影响。AG14361增加topotecan和temozolomide的抗增殖效应,抑制LoVo细胞从γ辐射损伤中恢复。

动物实验[2]:

动物模型

6-8周龄的老年雌性裸鼠

剂量

30 mg/kg,腹腔内给药

应用

小鼠在移植ES细胞一天前给药,持续9天。和对照组相比,BRCA1-/- ES源性肿瘤的形成减少了90%,而BRCA1+/+ ES源性肿瘤只减少了22%。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Calabrese C R, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly (ADP-ribose) polymerase-1 inhibitor AG14361[J]. Journal of the National Cancer Institute, 2004, 96(1): 56-67.

[2]. De Soto J A, Wang X, Tominaga Y, et al. The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors[J]. Int J Biol Sci, 2006, 2(4): 179-185.

生物活性

AG14361 is a potent inhibitor of PARP1 with Ki of <5 nM.
Targets PARP1          
IC50 < 5 nM (Ki)          

质量控制

化学结构

AG-14361

相关生物数据

AG-14361