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LY2835219

现货
Catalog No.
A1794
CDK4/6抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,000.00
现货
5mg
¥ 800.00
现货
25mg
¥ 1,800.00
现货
100mg
¥ 4,500.00
现货

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Background

LY2835219 is a selective and orally available dual cyclin-dependent kinases 4/6 (CDK4/6) inhibitor that potently inhibits the activities of CDK4 and CDK6 with the half maximal inhibition concentration IC50 values of 2 nM and 10 nM respectively [1].

LY2835219 has also been found to inhibit Rb phosphorylation both in vivo and in vitro leading to specific cell arrest at G1 phase as well as the inhibition of tumor growth [1].

Since the blood brain barrier (BBB) is a major obstacle for the effective treatment of primary brain tumors and brain metastases, LY2835219, which is able to cross the BBB, has the potential to inhibit intracranial tumor growth alone or in combination with other agents [1].

References:
[1] Concepcion Sanchez-Martinez, Lawrence M. Gelbert, Harlan Shannon, Alfonso De Dios, Brian A. Staton, Rose T. Ajamie, Geri Sawada, Graham N. Wishart and Thomas J. Raub. LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B234.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt602.7
Cas No.1231930-82-7
FormulaC27H32F2N8.CH4O3S
Solubility≥30.15mg/mL in DMSO
Chemical NameN-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine;methanesulfonic acid
SDFDownload SDF
Canonical SMILESCCN1CCN(CC1)CC2=CN=C(C=C2)NC3=NC=C(C(=N3)C4=CC5=C(C(=C4)F)N=C(N5C(C)C)C)F.CS(=O)(=O)O
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

激酶实验[1]:

结合实验

人Rb蛋白含有氨基酸773至928,通过使用人Rb蛋白的c-末端片段作为底物进行放射性-滤光片结合测定来测定CDK4和CDK6的活性。在昆虫细胞中表达并纯化人CDK4/cyclin D1和CDK6/cyclin D1复合物。将LY2835219以1:3的比例在20%的DMSO连续稀释,以20 μM为起始浓度生成10点曲线。将单独的20%的DMSO缓冲液作为对照组;使用500 mM EDTA测定不存在酶活性时的背景水平。使用ActivityBase软件(IDBS)进行4参数对数曲线拟合从而生成IC50值。进行动力学分析,使用一定范围的ATP浓度,并且通过使用GraphPad Prism拟合竞争性抑制剂的Michaelis-Menten方程来确定CDK4/cyclin D1和CDK6/cyclin D1的Ki值。

细胞实验[1]:

细胞系

Colo-205结肠癌细胞系,MDA-MB-361和MCF10A 乳腺癌细胞系, MV4-11 AML 细胞

溶解方法

该化合物在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

24 h

实验结果

LY2835219是一种选择性和口服可用的周期蛋白依赖性激酶4/6(CDK4/6)抑制剂。LY2835219(6000 nM)抑制Rb磷酸化,IC50值为120 nM,针对G1细胞阻滞(2 N DNA含量)的EC50值为72 nM。

动物实验[1]:

动物模型

colo-205肿瘤异种移植小鼠

剂量

12.5 mg/kg, 25 to 100mg/kg

溶解方法

含1%羟乙基纤维素+ 0.1%消泡剂的25mM PB pH 2中配制,通过灌胃法(终体积0.2 mL)口服给药。

实验结果

LY2835219在colo-205中介导CDK4/6抑制、细胞周期停滞和肿瘤生长抑制(TGI),并抑制CDK4/6对Rb的磷酸化。LY2835219显著抑制肿瘤生长,100 mg/kg高剂量的LY2835219具有良好耐受性,在治疗期间或之后没有造成体重损失或其它毒性迹象。

注意事项

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.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]. Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs, 2014, 32(5): 825-837.

生物活性

描述 LY2835219是一种有效的和选择性的CDK4和CDK6抑制剂,IC50值分别为2 nM和10 nM。
靶点 CDK4 CDK6        
IC50 2 nM 10 nM        

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