PHA-848125
(Synonyms: PHA-848125) 目录号 : GC15588
An inhibitor of Cdks
Cas No.:802539-81-7
Sample solution is provided at 25 µL, 10mM.
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PHA-848125 is a potent and ATP-competitive Cdk2/cyclin A inhibitor with an IC50 value of 45 nM. PHA-848125 also inhibited Cdk7/cyclin H, Cdk4/cyclin D1, Cdk5/p35, Cdk2/cyclin E and Cdk1/cyclin B with less potency (IC50= 0.15 µM, 0.16 µM, 0.265 µM, 0.363 µM and 0.398 µM, respectively). [1]
CDK (cyclin-dependent kinase) is a group of serine/threonine kinases. It is activated by binding to cyclin and participates in the regulation of cell cycle.
In cells treated with PHA-848125, hyperphosphorylated form of CDK substrate—retinoblastoma protein (pRb) was reduced and hypophosporylated from of pRb was accumulated. It further indicated inhibition effect of PHA-848125 on CDK2 activity. [1]
In human ovarian A2780 xenogaft mouse model, 20, 30 and 40mg/kg of PHA-848125 were each administrated orally twice a day for 10 days. PHA-848125 inhibited A2780 tumor growth up to 91% at 40 mg/kg dose. [1]
Reference:
1. Brasca MG, Amboldi N, Ballinari D et al. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem. 2009 Aug 27;52(16):5152-63.
| Cell experiment [1,2]: | |
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Cell lines |
GL-Mel cells |
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Preparation method |
The solubility of this compound in DMSO is > 23.1 mg/mL. 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 |
0.156 or 0.625 μM, 72 hours |
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Applications |
Exposure of GL-Mel cells to 0.156 μM PHA-848125 induced a moderate increase in the G1 fraction with no significant changes concerning the S and the G2/M fractions. Treatment with 0.625 μM PHA-848125 caused instead a marked accumulation of the cells in the G1 phase, accompanied by a concomitant strong reduction of the percentage of cells in the S and G2/M phases. PHA-848125 slightly up-regulated the expression of p53 in GL-Mel cells. PHA-848125 showed antiproliferative activity against a panel of 145 tumor cell lines established from different solid tumors and a further 44 cell lines derived from leukemias and lymphomas. |
| Animal experiment [2,3]: | |
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Animal models |
K-Ras(G12D)LA2 mice, human ovarian carcinoma A2780 xenografted mouse model, human xenograft tumors s.c. implanted in athymic mice |
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Dosage form |
Oral administration, 40 mg/kg twice daily for 10 days |
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Application |
In the preclinical xenograft A2780 human ovarian carcinoma model, PHA-848125 showed good efficacy and was well tolerated upon repeated daily treatments. Treatment of K-Ras(G12D)LA2 mice with PHA-848125 (40 mg/kg twice daily for 10 days) resulted in significant tumor growth inhibition at the end of the treatment. PHA-848125 (40 mg/kg orally twice a day × 5 days, repeated for four cycles) significantly increased survival time in two models of human primary disseminated leukemias. |
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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]. Caporali S, Alvino E, Starace G, et al. The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound[J]. Pharmacological research, 2010, 61(5): 437-448. [2]. Albanese C, Alzani R, Amboldi N, et al. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy[J]. Molecular cancer therapeutics, 2010, 9(8): 2243-2254. [3]. Degrassi A, Russo M, Nanni C, et al. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-RasG12DLA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging[J]. Molecular cancer therapeutics, 2010, 9(3): 673-681. | |
| Cas No. | 802539-81-7 | SDF | |
| 别名 | PHA-848125 | ||
| 化学名 | N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,3-h]quinazoline-3-carboxamide | ||
| Canonical SMILES | CC1(CC2=CN=C(N=C2C3=C1C(=NN3C)C(=O)NC)NC4=CC=C(C=C4)N5CCN(CC5)C)C | ||
| 分子式 | C25H32N8O | 分子量 | 460.57 |
| 溶解度 | ≥ 23.05mg/mL in DMSO | 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 | 2.1712 mL | 10.8561 mL | 21.7122 mL |
| 5 mM | 0.4342 mL | 2.1712 mL | 4.3424 mL |
| 10 mM | 0.2171 mL | 1.0856 mL | 2.1712 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