MK-4827
(Synonyms: 尼拉帕尼; MK-4827) 目录号 : GC17802
An orally bioavailable PARP1/2 inhibitor
Cas No.:1038915-60-4
Sample solution is provided at 25 µL, 10mM.
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.
| Kinase experiment [1]: | |
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Kinase assays |
The reaction was conducted as for PARP-1 and PAPP-2 and included 0.3 nM of PARP-2, 4.4 x 105 DPM of [3H]-NAD and 7.5 uM NAD. |
| Cell experiment [1]: | |
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Cell lines |
MDA-MB-436 and CAPAN-1 cell lines, human prostate epithelial (PREC) cells, Human mammary epithelial (HMEC) cells |
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Preparation method |
Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0-20000 nM |
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Applications |
In MDA-MB-436 cells carrying BRCA-1 mutations, MK-4827 displayed CC50 = 18 nM, while in CAPAN-1 cells with BRCA-2 mutant, MK-4827 displayed CC50 = 90 nM. In contrast, normal human prostate and mammary epithelial cells were resistant to MK-4827, displaying antiproliferative effects in the micromolar range, thereby demonstrating the very high selective cytotoxicity from these PARP inhibitors in BRCA-1 and -2 mutant cancer cells compared to surrounding tissue. |
| Animal experiment [2]: | |
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Animal models |
Female nude mice (Ncr Nu/Nu) xenograft model |
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Dosage form |
25 mg/kg given twice daily or 50 mg/kg MK-4827 given once daily, oral |
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Application |
The in vivo efficacy of MK-4827 was demonstrated in a BRCA-1 mutant MDA-MB-436 xenograft mode. When tumors reached an average volume of 150 mm3, mice were treated with MK-4827, dosing orally at either 100 mg/kg q.d. or 50 mg/kg b.i.d. Tumor regression was observed with both dosing regimes, and both were well tolerated, with no mortality. Less than 10% body weight loss was seen during the experiment. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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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. | |
| Cas No. | 1038915-60-4 | SDF | |
| 别名 | 尼拉帕尼; MK-4827 | ||
| 化学名 | 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide | ||
| Canonical SMILES | C1CC(CNC1)C2=CC=C(C=C2)N3C=C4C=CC=C(C4=N3)C(=O)N | ||
| 分子式 | C19H20N4O | 分子量 | 320.39 |
| 溶解度 | ≥ 32 mg/mL in DMSO, ≥ 50.9 mg/mL in EtOH with gentle warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.1212 mL | 15.606 mL | 31.212 mL |
| 5 mM | 0.6242 mL | 3.1212 mL | 6.2424 mL |
| 10 mM | 0.3121 mL | 1.5606 mL | 3.1212 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet