ATR/ATM kinases can phosphorylate a broad and overlapping catalogue of several thousand substrates in DNA damage signaling. The kinase activity of ATR, activated by single-stranded DNA (ssDNA) coated with replication protein A (RPA), is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). VE-821 is a potent and selective ATR inhibitor with Ki value of 13nM. Pre-treatment with 10μM inhibited the H2AX phosphorylation at an early time point after exposure to the S phase poisons cisplatin and gemcitabine, but not the double-strand breaks inducers etoposide and ionizing radiation in HFL1 cells, suggesting the selective inhibition on ATR by VE-821. It showed strong synergy with genotoxic agents from multiple classes, most marked with cisplatin and carboplatin, in HCT116 cancer cells, but not in normal cell lines. In addition, cisplatin and VE-821 clearly acted synergistically in the ATM-null cells but not in the normal cells, indicating the reliance on ATR for survival from DNA damage in cancer cells with defects in ATM signaling[1].
作用机制
VE-821 is a potent ATP-competitive inhibitor of ATR.[1]
VE-821 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
CAL72
Growth Inhibition Assay
IC50～0.8 μM
25593184
HCT-116 p53-/-
1/3/10 μM
Cytotoxicity Assay
1 h
potentiates the cytotoxicity of both camptothecin and LMP-400
25269479
HCT-116 p53+/+
1/3/10 μM
Cytotoxicity Assay
1 h
potentiates the cytotoxicity of both camptothecin and LMP-400
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