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-822 is a close analog of VE-821, possessing a marked potency against ATR with Ki value < 0.2nM, as well as cell IC50 value of 19nM. The cell study showed that VE-822 can attenuate ATR signaling pathway and reduce survival in tumor cells in response to XRT and gemcitabine. Treatment with VE-822 (80nM) reduced pChk1-Ser345, as the major marker for ATR inhibition, after gemcitabine (100 nM), XRT (6 Gy) or both in MiaPaCa-2 and PSN-1 cells or in vivo study, alone with dramatically reduced survival of these two tumor cells (but not in normal cells). 1h pre-treatment with 80nM VE-822 increased XRT-induced residual γH2AX and 53BP1 foci, whereas no effect on VE-822 alone, suggesting the enhancement of residual DNA damage by VE-822 in vitro. Oral administration with VE-822 at dose of 60mg/kg enhanced the therapeutic efficacy of radiation (XRT) in MiaPaCa-2 and PSN-1 xenograft models, as well as enhanced tumor response in combination with XRT and gemcitabine in PSN-1 xenografts[1].
作用机制
VE-822 is a close analog of VE-821, which acts as an ATP-competitive inhibitor of ATR.[1]
Berzosertib 细胞研究
细胞系
浓度
检测类型
检测时间
活性说明
数据源
HCK1T-HPV16
0.5 nM
Function Assay
24 h
increases the levels of E1
25717108
HCK1T-HPV16
0.5 nM
Function Assay
24 h
enhances E1-dependent replication of the HPV16 genome
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