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LY2857785

现货
Catalog No.
B8002
CDK9抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 2,210.00
现货
10mg
¥ 3,780.00
现货
50mg
¥ 11,400.00
Ship with 10-15 days
100mg
¥ 199,500.00
Ship with 10-15 days

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Background

LY2857785 was identified as a type I reversible and competitive ATP kinase inhibitor against CDK9 and other transcription kinases CDK8 and CDK7.[1,2]

Cdk7 acts as a Cdk-activating kinase and regulate transcription. Cdk8 and Cdk9 regulate transcription via phosphorylation of the RNA polymerase II carboxyl terminal domain. The Cdk9-related pathway performs an important role in several biological processes, such as cell growth, proliferation, protection from apoptosis and differentiation. These kinases are reported dys-regulation in some cancers. [2]

Transcription activation requires phosphorylation of a carboxyl-terminal domain, by a variety of kinases including CDK7, CDK8, and CDK9. By inhibiting these kinases, LY2857785 has unique transcription inhibitor activity. LY2857785 dramatically inhibited XIAP protein level in MV-4-11 and other hematologic cancer cells. It also can significantly reduce RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. [1]

LY2857785 potently inhibits a carboxyl-terminal domain phosphorylation and exhibits antitumor efficacy in orthotopic models of leukemia. LY2857785 inhibits the growth of leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. LY2857785 may be used in treating patients with hematologic tumors, particularly AML and CLL. [1]

References:
[1] Yin T, Lallena MJ, Kreklau EL etal. , A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol Cancer Ther. 2014 Jun;13(6):1442-56.
[2] Romano G1, Giordano A.   Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and human diseases. Cell Cycle. 2008 Dec;7(23):3664-8.

Chemical Properties

StorageDesiccate at -20°C
M.Wt448.6
Cas No.1619903-54-6
FormulaC26H36N6O
Solubility≥13.87mg/mL in EtOH with gentle warming
Chemical Name(1r,4r)-N1-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-N4-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diamine
SDFDownload SDF
Canonical SMILESCN1C(C(C)C)=C(C(C=C2)=N1)C=C2C3=NC(N[C@H]4CC[C@H](NC5CCOCC5)CC4)=NC=C3
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

酶学实验 [1]:

结合实验

CDK7和CDK9反应混合物含有10 mmol/L Tris-HCl(pH 7.4),10 mmol/L HEPES,5 mmol/L DTT,10 μmol/L ATP,0.5 μCi33p-ATP,10 mmol/L MnCl2,150 mmol/L NaCl,0.01%Triton X-100,2%二甲基亚砜(DMSO),0.05 mmol/L CDK7/9ptide和2 nmol/L CDK7/Mat1/细胞周期蛋白H(14-476M)或2 nmol/L CDK9/cyclin T1(14-685M)。CDK8/细胞周期蛋白C反应在HEPES 30 mmol/L,DTT 2 mmol/L,MgCl2 5 mmol/L,0.015%Triton X-100,5 μmol/L ATP和400 nmol/L(含20 nmol/L的RBER-CHKStide)中进行。化合物在DMSO中3倍梯度稀释。反应在96孔聚苯乙烯板中进行。将反应物在室温下孵育60分钟,然后用10%H3PO4或10%三氯乙酸(TCA)终止。对于结合测定,将反应转移到96孔过滤板中,并通过Microbeta闪烁计数器测量。

细胞实验 [1]:

细胞系

人骨髓髓细胞祖细胞

溶解方法

溶于DMSO。为了获得更高浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

用不同浓度的化合物处理细胞,持续时间为4至24小时。

应用

LY2857785抑制血液肿瘤细胞(人骨髓髓细胞祖细胞)增殖。

动物实验 [1]:

动物模型

人类癌细胞U87MG,MV-4-11,A375和HCT116大鼠异种移植模型

剂量

4、8、18 mg/kg,静脉注射,3天一次

应用

LY2857785在临床前肿瘤模型(U87MG,MV-4-11,A375和HCT116大鼠异种移植模型)中显示出有效的抗肿瘤生长功效。

注意事项

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] Yin T, et al. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol Cancer Ther. 2014 Jun;13(6):1442-56.

质量控制

化学结构

LY2857785