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BMN 673

现货
Catalog No.
A4153
PARP抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,300.00
现货
10mg
¥ 2,570.00
现货
50mg
¥ 6,180.00
现货

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Background

BMN673 is a potent and selective PARP1/2 inhibitor with Ki of 1.2 and 0.9 nM, respectively 1. It had no effect on panels of 72 receptors, ion channels, and enzymes 1. BMN673 showed IC50 value of 0.57 nM in enzymatic assay of PARP1 1. In in vitro assay, it exhibited greater potency than other existing PARP inhibitors, such as veliparib, rucaparib, and olaparib 2. It is also much more potent at trapping PARP-DNA complexes than other PARP inhibitors 3.

BMN673 has shown anti-tumor activity both in vitro and in vivo. It inhibited proliferation of tumor cells and xenografts with defects in homologous recombination 1. The combination of BMN673 and DNA-damaging agents demonstrated synergistic anti-tumor effects 1. In addition, study showed that the expression levels of DNA repair proteins and status of PI3K pathway predict response to BMN673 in small cell lung cancer 4.

BMN673 is currently under investigation in multiple clinical trials for advanced solid tumors or hematological malignancies, either as monotherapy or in combination with other anti-tumor agents.

References:
1. Shen Y, Rehman FL, Feng Y et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res 2013; 19: 5003-5015.
2. Cardnell RJ, Byers LA. Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung Cancer--Response. Clin Cancer Res 2014; 20: 2237.
3. Murai J, Huang SY, Renaud A et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13: 433-443.
4. Cardnell RJ, Feng Y, Diao L et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res 2013; 19: 6322-6328.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt380.35
Cas No.1207456-01-6
FormulaC19H14F2N6O
Solubility≥19.0 mg/mL in DMSO, ≥14.2 mg/mL in EtOH with ultrasonic and warming, <2.41 mg/mL in H2O
Chemical Name(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one
SDFDownload SDF
Canonical SMILESFC1=CC2=C3C([C@H](C4=NC=NN4C)[C@@H](C(C=C5)=CC=C5F)NC3=C1)=NNC2=O
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]:

抑制活性

对于PARP抑制剂Ki测定,在含有0.5 U PARP1酶、0.25x活化的DNA、0.2 mCi[3H] NAD和5 mmol/L冷NAD(Sigma)的96孔FlashPlate中,以50 mL的终体积进行酶测定,反应液中含有10%甘油(v/v)、25 mmol/L HEPES、12.5 mmol/L MgCl2、50 mmol/L KCl、1 mmol/L二硫苏糖醇(DTT)和0.01%NP-40(v/v),pH 7.6。通过将1–100 mmol/L NAD加入含有或不含抑制剂的PARP反应混合物中引发反应,并在室温下孵育1分钟。然后向每个孔中加入50 μl冰冷的20%三氯乙酸(TCA)以终止反应。将板密封并在室温下振摇120分钟,然后离心。使用Top-Count测定结合到FlashPlate的放射性信号。使用不同底物浓度(1-100 mmol/L NAD)的Michaelis-Menten方程确定PARP1的Km值。根据以下公式从酶抑制曲线计算化合物的Ki:Ki ? IC50/[1? (substrate)/Km]。用相同的实验方案测定PARP2酶的Km和化合物的Ki,使用30 ng PARP2、0.25x活化的DNA、0.2mCi [3H] NAD和20 mmol/L冷NAD在室温下反应30分钟。

细胞实验 [2]:

细胞系

SCLC细胞系

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

24 h-96 h

实验结果

在11个SCLC细胞系中,BMN 673表现出有效的抑制作用,IC50 为1.7到15 nmol/L,均在临床上可实现的范围内。此外,对BMN673的敏感性与DNA修复蛋白表达和PI3K途径活性相关。

动物实验[1]:

动物模型

MX-1肿瘤皮下异种移植物裸鼠。

给药剂量

口服,每天两次,连续28天。

实验结果

BMN 673抑制小鼠中MX-1异种移植物的生长,6只小鼠中的4只被完全抑制。0.33和0.1 mg/kg BMN 673具有良好耐受性,没有动物致死性。

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. Shen Y, Rehman FL, Feng Y et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013 Sep 15;19(18):5003-15.

2. Cardnell RJ, Feng Y, Diao L et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res. 2013 Nov 15;19(22):6322-8.

生物活性

BMN673是一种有效的和选择性的PARP1/PARP2抑制剂,Ki值分别为1.2和0.9 nM。.
靶点 PARP          
IC50 0.58 nM          

质量控制

化学结构

BMN 673

相关生物数据

BMN 673

相关生物数据

BMN 673