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MK-4827

现货
Catalog No.
A3617
PARP-1/-2抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 950.00
现货
10mg
¥ 1,680.00
现货
50mg
¥ 5,700.00
现货
100mg
¥ 7,700.00
现货

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Background

MK-4827 is a novel, selective and orally bioavailable PARP1/PARP2 inhibitor with IC50 of 3.8 nM and 2.1 nM, respevctively.MK-4827 has shown great activity against cancer cells with mutant BRCA-1 and BRCA-2; >330-fold selective against PARP3, V-PARP and Tank1 [1].

Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 belong to a family of enzymes (PARP) that, using β-NAD+as a substrate, catalyze poly(ADP-ribosyl)ation of proteins, synthesize and transfer ADP-ribose polymers onto glutamate, aspartate or lysine residues of acceptor proteins, modifying their functional properties. PARP inhibitors compete with NAD+ at the highly conserved enzyme active site, making them new potential therapeutic strategies as chemo- and radio-potentiation and for the treatment of cancers with specific DNA repair defects as single-agent therapies [2].

In vitro: MK-4827displayed excellent PARP 1 and 2 inhibition with IC50 of 3.8 and 2.1 nM, respectively. In a whole cell assay, MK-4827 inhibited PARP activity with EC50 of 4 nM. MK-4827 also inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range[1].

In vivo: In a variety of human tumor xenografts of differing p53 status,MK-4827 showed high potential to improve the efficacy of radiotherapy,such as Calu-6 (p53 null), A549 (p53 wild-type [wt]) and H-460 (p53 wt) lung cancers and triple negative MDA-MB-231 human breast carcinoma [3].

References:
[1] Jones P1,Altamura S,Boueres J,Ferrigno F, et al.  Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem.2009 Nov 26;52(22):7170-85.
[2] Yelamos J, Farres J, Llacuna L, et al.  PARP-1 and PARP-2: New players in tumourdevelopment[J]. Am J Cancer Res, 2011, 1(3): 328-346.
[3] Wang L1,Mason KA,Ang KK,Buchholz T,Valdecanas D,Mathur A,Buser-Doepner C,Toniatti C,Milas L.  MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs.2012 Dec;30(6):2113-20.

Chemical Properties

StorageStore at -20°C
M.Wt320.39
Cas No.1038915-60-4
FormulaC19H20N4O
SynonymsNiraparib; MK 4827; MK4827
Solubility≥32 mg/mL in DMSO, ≥50.9 mg/mL in EtOH with gentle warming, <2.45 mg/mL in H2O
Chemical Name2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide
SDFDownload SDF
Canonical SMILESC1CC(CNC1)C2=CC=C(C=C2)N3C=C4C=CC=C(C4=N3)C(=O)N
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

酶学实验 [1]:

激酶检测

用于测定PARP-1 和 PAPP-2酶学活性的反应是在含有0.3 纳摩尔的 PARP-1/2、 4.4 x 105 DPM的[3H]-NAD 以及 7.5 微摩尔的NAD体系中进行的。

细胞实验 [1]:

细胞系

MDA-MB-436 和CAPAN-1细胞系;人前列腺上皮(PREC)细胞以及人类乳腺上皮(HMEC)细胞

溶解方法

在DMSO中可溶。为了获得更高浓度,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

0-20000 nM

应用

在携带BRCA-1突变的MDA-MB-436细胞中,MK-4827显示其CC50 为 18 nM,而在具有BRCA-2突变的CAPAN-1细胞中,MK-4827显示CC50 为 90nM。 相比之下,正常人前列腺和乳腺上皮细胞对MK-4827具有抗性,在微摩尔水平才有抗增殖作用,从而证明与周围组织相比,PARP抑制剂对BRCA-1和-2突变型癌细胞具有非常高的选择性细胞毒性。

动物实验 [2]:

动物模型

雌性荷瘤小鼠(Ncr Nu/Nu)模型

剂量

25 mg/kg,一天两次或者50 mg/kg,一天一次;口服

应用

在BRCA-1突变的MDA-MB-436荷瘤小鼠模型中显示MK-4827的体内疗效。当肿瘤平均体积达到150mm 3时,用MK-4827以100mg / kg q.d. 或50mg / kg b.i.d.的剂量口服给药治疗荷瘤小鼠。结果表明两种给药方式均可以使肿瘤消退,两者耐受性良好,无死亡,而且实验期间体重减轻不到10%。

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] Jones P, Altamura S, Boueres J, Ferrigno F, et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.

[2] Wang L, Mason KA, Ang KK,Buchholz T,Valdecanas D, Mathur A, Buser-Doepner C, Toniatti C, Milas L. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs. 2012 Dec;30(6):2113-20.

生物活性

MK-4827 is a potent, selective inhibitor of PARP 1 and PARP 2 with IC50 of 3.8 and 2.1 nM, respectively.
Targets PARP1 PARP2        
IC50 3.8 nM 2.1 nM        

质量控制

化学结构

MK-4827