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AT7519

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Chemical Structure| 844442-38-2 同义名 : AT7519M
CAS号 : 844442-38-2
货号 : A485554
分子式 : C16H17Cl2N5O2
纯度 : 98+%
分子量 : 382.245
MDL号 : MFCD13184820
存储条件：

粉末 Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(130.81 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

2% DMSO+30% PEG 300+2% Tween 80+water 1 mg/mL

生物活性
靶点

  • CDK5

    CDK5/p35, IC50:13 nM

  • CDK4

    CDK4/CyclinD1, IC50:100 nM

  • CDK2

    CDK2/CyclinA, IC50:47 nM

  • CDK6

    CDK6/CyclinD3, IC50:170 nM
描述 The CDKs (cyclin dependent kinases), as direct regulators of specific phases of the cell cycle, can control cellular proliferation and transcription with their activating cyclin partners and subunit inhibitors. Thus, the inhibition of CDKs can be assessed with monitoring the phosphorylation state of specific substrates. For example, decreased phosphorylation of the CDK1 substrate PP1 a (T320) and the CDK2 substrates Rb (T821) and NPM (T199) can indicated the inhibition of the CDKs. Decreased phosphorylation of pSer5 and pSer2 of RNA pol II CTD would indicate inhibition of CDKs 7 and 9, respectively. AT7519 is a pan-CDKs inhibitor with IC50 values of 47, 13, <10 nM for CDK2/CyclinA, CDK5/p35 and CDK9/CyclinT, and modest activity against CDK1/CyclinB, CDK3/CyclinE, CDK4/CyclinD1 and CDK6/CyclinD3 with IC50 values of 210, 360, 100 and 170 nM, respectively (measured by in vitro kinase assays)[1]. Treatment with 0.05-1uM AT7519 for 24h was sufficient to inhibit phosphorylation of the CDK1 substrate PP1a (T320) and the CDK2 substrates Rb (T821) and NPM (T199) in HCT116 cells[2]. AT7519 on concentration of 0.5 μM induced rapid dephosphorylation at both RNA pol II CTD at both the serine 2 and serine 5 sites[1]. AT7519 showed antiproliferative activity and apoptosis-induction in a panel of human tumor cell lines, including ovarian carcinoma, lung carcinoma, breast carcinoma, uterine sarcoma, leukemia and lymphoma, with IC50 values ranging from 40 to 940nM. AT7519 with concentration of 250-1000nM can induce G0-G1 and G2-M cell cycle blockade in HCT116 cells. Intraperitoneal or intravenous administration of 9.1mg/kg AT7519 twice a day for 9 consecutive days achieved completely tumor regression on day 15 in HCT116 tumor xenografts[2]. Phase 2 studies of AT7519 treatment for mantle cell lymphoma and chronic lymphocytic leukemia have been completed (see in https://www.clinicaltrials.gov/).
作用机制 The inhibition of CDK1 by AT7519 is competitive with ATP.
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
A2780 cells Proliferation assay 72 h Antiproliferative activity against human A2780 cells assessed as cell viability after 72 hrs by alamar blue assay, IC50=0.35 μM 18656911
HCT116 cells Cytotoxic assay 72 h Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by Alamar blue assay, IC50=0.08 μM 26115571
MRC5 cells Proliferation assay 72 h Antiproliferative activity against human MRC5 cells assessed as cell viability after 72 hrs by alamar blue assay, IC50=0.98 μM 18656911
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.62mL

0.52mL

0.26mL

13.08mL

2.62mL

1.31mL

26.16mL

5.23mL

2.62mL
参考文献

[1]Santo L, Vallet S, et al. AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. Oncogene. 2010 Apr 22;29(16):2325-36.

[2]Squires MS, Feltell RE, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009 Feb;8(2):324-32.

[3]Dolman ME, Poon E, et al. Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. Clin Cancer Res. 2015 Nov 15;21(22):5100-9.