PHA-848125
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
PHA-848125是一种有效的ATP竞争性Cdk2/cyclin A抑制剂,其IC50值为45 nM。PHA-848125也抑制Cdk7/cyclin H、Cdk4/cyclin D1、Cdk5/p35、Cdk2/cyclin E和Cdk1/cyclin B,但效果弱于对Cdk2/cyclin的抑制作用,(IC50 = 0.15 M、0.16 M、0.265 M、0.363 M和0.398 M)[1]。
CDK(细胞周期蛋白依赖性激酶)是一组丝氨酸/苏氨酸激酶。CDK通过结合细胞周期蛋白而被激活,参与细胞周期调控。
在PHA-848125处理的细胞中,CDK底物视网膜母细胞瘤蛋白(pRb)的过度磷酸化形式减少,而pRb以低磷酸化形式积累。此外,此实验还表明,PHA-848125对CDK2活性具有抑制作用。[1]
在人卵巢A2780细胞异种移植小鼠模型中,口服给予20、30和40 mg/kg的PHA-848125,每天两次,持续10天。在40 mg/kg的剂量下,PHA-848125抑制高达91%的A2780肿瘤生长[1]。
参考文献:
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.
Physical Appearance | A solid |
Storage | Store at -20°C |
M.Wt | 460.57 |
Cas No. | 802539-81-7 |
Formula | C25H32N8O |
Solubility | ≥23.05 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O |
Chemical Name | N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,3-h]quinazoline-3-carboxamide |
SDF | Download SDF |
Canonical SMILES | CC1(CC2=CN=C(N=C2C3=C1C(=NN3C)C(=O)NC)NC4=CC=C(C=C4)N5CCN(CC5)C)C |
运输条件 | 蓝冰运输或根据您的需求运输。 |
一般建议 | 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。溶液形式一般不宜长期储存,请尽快用完。 |
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. |
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 |