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PHA-848125

现货
Catalog No.
A8501
有效的ATP竞争性CDK抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 2,200.00
Ship with 10-15 days
5mg
¥ 1,900.00
现货
10mg
¥ 2,600.00
现货

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Background

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.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt460.57
Cas No.802539-81-7
FormulaC25H32N8O
Solubility≥23.05mg/mL in DMSO
Chemical NameN,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,3-h]quinazoline-3-carboxamide
SDFDownload SDF
Canonical SMILESCC1(CC2=CN=C(N=C2C3=C1C(=NN3C)C(=O)NC)NC4=CC=C(C=C4)N5CCN(CC5)C)C
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 [1,2]:

细胞系

GL-Mel细胞

溶解方法

该化合物在DMSO中的溶解度大于23.1 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

0.156或0.625 μM,72小时

应用

在GL-Mel细胞中,PHA-848125(0.156 μM)诱导G1细胞的适度增加,对S和G2/M期没有明显影响。PHA-848125(0.625 μM)处理导致G1期细胞显著积累,同时伴随着S期和G2/M期细胞百分比的强烈降低。PHA-848125略微上调了GL-Mel细胞中p53的表达。针对来自不同实体瘤的145个肿瘤细胞系和另外44个源自白血病和淋巴瘤的细胞系,PHA-848125显示出抗增殖活性。

动物实验 [2,3]:

动物模型

K-Ras(G12D)LA2小鼠,人卵巢癌A2780异种移植小鼠模型,皮下植入人异种移植肿瘤的无胸腺小鼠

给药剂量

口服给药,40 mg/kg,每日两次,持续10天

应用

在临床前异种移植物A2780人卵巢癌模型中,PHA-848125显示出良好的疗效,并且在重复的日常处理中耐受性良好。在K-Ras(G12D)LA2小鼠中,使用PHA-848125(40 mg/kg)治疗,每天两次,持续10天,治疗结束时显著抑制肿瘤生长。在两种模型的人类原发性弥散性白血病中,口服PHA-848125(40 mg/kg),每天两次×5天,重复四个周期,显著增加小鼠存活时间。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

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.

生物活性

Description Milciclib(PHA-848125)是有效的ATP竞争性CDK抑制剂,对CDK2的IC50值为45 nM。
靶点 CDK2/CyclinA TrkA CDK7/CyclinH CDK4/CyclinD1 CDK5/p35  
IC50 45 nM 53 nM 150 nM 160 nM 265 nM  

质量控制

质量控制和MSDS

批次:

化学结构

PHA-848125