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.
PHA-767491 hydrochloride 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
human HCT15 cells
Proliferation assay
72 h
Antiproliferative activity against human HCT15 cells expressing p53 gene after 72 hrs by proliferative assay, IC50=3.81 μM
搜索
