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PHA-767491 hydrochloride

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Chemical Structure| 942425-68-5 同义名 : -
CAS号 : 942425-68-5
货号 : A669599
分子式 : C12H12ClN3O
纯度 : 98%
分子量 : 249.696
MDL号 : MFCD11519962
存储条件：

粉末 Inert atmosphere,Room Temperature

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 16 mg/mL(64.08 mM)，配合低频超声，并水浴加热至45℃助溶，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

H2O: 50 mg/mL(200.24 mM)，配合低频超声助溶
动物实验配方：

5% DMSO+30% PEG 300+2% Tween 80+water 1 mg/mL

生物活性
靶点

  • CDK5

    CDK5, IC50:460 nM

  • CDK2

    CDK2, IC50:240 nM

  • CDK9

    CDK9, IC50:34 nM

  • Cdc

    Cdc7, IC50:10 nM

  • CDK1

    CDK1, IC50:250 nM
描述 Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. PHA-767491 is an effective, ATP-competitive, dual Cdc7/CDK9 inhibitor with IC50s of 10 nM and 34 nM, respectively. Cell proliferation was inhibited in a panel of 61 human cell lines challenged with low micromolar concentrations of PHA-767491, with an average IC50 value of 3.17 mM and less than 10 mM in all cases. In a smaller panel of 17 different cell types, using sub-G1 DNA content as a parameter of apoptosis, 24 h of exposure to either 5 or 10 mM PHA-767491 was sufficient to cause cell death. Importantly, PHA-767491 is capable of preventing duplication, and it can kill both p53-positive and p53-negative tumor cells of different origins. Treatment with 5 mM PHA-767491 for 6 to 9 hours in HeLa cells was necessary to observe a marked decrease in the number of bromodeoxyuridine (BrdU)-positive cells. After intravenous administration at two dose levels of 20 and 30 mg/kg twice a day for five consecutive days in nude mice carrying subcutaneous implanted tumors, a dose-dependent reduction in tumor volume with respect to vehicle-treated animals was observed[3].
作用机制 PHA-767491 competes with ATP for binding site, thus behaving as a pure ATP competitor.
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human A2780 cells Proliferation assay 72 h Antiproliferative activity against human A2780 cells expressing p53 gene after 72 hrs by proliferative assay, IC50=1.07 μM 18469809
human COLO205 cells Proliferation assay 72 h Antiproliferative activity against human COLO205 cells after 72 hrs by luciferase based assay, IC50=1.5 μM 19115845
human HCT116 cells Proliferation assay 72 h Antiproliferative activity against human HCT116 cells expressing p53 gene after 72 hrs by proliferative assay, IC50=0.97 μM 18469809
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

4.00mL

0.80mL

0.40mL

20.02mL

4.00mL

2.00mL

40.05mL

8.01mL

4.00mL
参考文献

[1]Natoni A, Murillo LS, et al. Mechanisms of action of a dual Cdc7/Cdk9 kinase inhibitor against quiescent and proliferating CLL cells. Mol Cancer Ther. 2011 Sep;10(9):1624-34.

[2]Swords R, Mahalingam D, et al. Cdc7 kinase - a new target for drug development. Eur J Cancer. 2010 Jan;46(1):33-40.

[3]Montagnoli A, Valsasina B, Croci V, Menichincheri M, Rainoldi S, Marchesi V, Tibolla M, Tenca P, Brotherton D, Albanese C, Patton V, Alzani R, Ciavolella A, Sola F, Molinari A, Volpi D, Avanzi N, Fiorentini F, Cattoni M, Healy S, Ballinari D, Pesenti E, Isacchi A, Moll J, Bensimon A, Vanotti E, Santocanale C. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008 Jun;4(6):357-65. doi: 10.1038/nchembio.90. Epub 2008 May 11. PMID: 18469809.