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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
UWB1 + B1
0.313 µM
6 days
VE-821 significantly reduced the IC50 of PARPi (olaparib) in resistant cells, indicating that ATRi can preferentially sensitize PARPi-resistant BRCA1-deficient cells to PARPi.
Genes Dev. 2017 Feb 1;31(3):318-332.
SYr12
0.313 µM
6 days
VE-821 significantly reduced the IC50 of PARPi (olaparib) in resistant cells, indicating that ATRi can preferentially sensitize PARPi-resistant BRCA1-deficient cells to PARPi.
Genes Dev. 2017 Feb 1;31(3):318-332.
SYr13
0.313 µM
6 days
VE-821 significantly reduced the IC50 of PARPi (olaparib) in resistant cells, indicating that ATRi can preferentially sensitize PARPi-resistant BRCA1-deficient cells to PARPi.
Genes Dev. 2017 Feb 1;31(3):318-332.
MHCC-97H cells
38.74 μM
VE821 significantly inhibited the proliferation, migration, and colony formation ability of MHCC-97H cells and enhanced apoptosis
J Exp Clin Cancer Res. 2022 Jan 8;41(1):17.
Hep3B cells
18.22 μM
VE821 significantly inhibited the proliferation, migration, and colony formation ability of Hep3B cells and enhanced apoptosis
J Exp Clin Cancer Res. 2022 Jan 8;41(1):17.
HeLa cells
10 μM
8 h
To examine the effect of VE-821 on MSL1 mRNA isoforms, results showed that VE-821 did not block MSL1 upregulation.
Cell Rep. 2021 Oct 12;37(2):109815.
U2OS cells
10 μM
8 h
To examine the effect of VE-821 on MSL1 mRNA isoforms, results showed that VE-821 did not block MSL1 upregulation.
Cell Rep. 2021 Oct 12;37(2):109815.
U2OS cells
10μM
24 h
To investigate the effect of VE-821 on micronuclei rupture, results showed that VE-821 reduced the fraction of cGAS+ micronuclei
Mol Cell. 2023 Oct 19;83(20):3642-3658.e4.
MDA-MB-231 cells
10μM
24 h
To investigate the effect of VE-821 on micronuclei rupture, results showed that VE-821 reduced the fraction of cGAS+ micronuclei
Mol Cell. 2023 Oct 19;83(20):3642-3658.e4.
HeLa cells
10μM
24 h
To investigate the effect of VE-821 on micronuclei rupture, results showed that VE-821 reduced the fraction of cGAS+ micronuclei
Mol Cell. 2023 Oct 19;83(20):3642-3658.e4.
AGS cells
1 μM, 2 μM, 5 μM
72 h
VE-821 significantly inhibited the proliferation of AGS cells and synergized with cisplatin to enhance its sensitivity.
Transl Oncol. 2023 Oct;36:101743.
MKN-45 cells
1 μM, 2 μM, 5 μM
72 h
VE-821 significantly inhibited the proliferation of MKN-45 cells and synergized with cisplatin to enhance its sensitivity.
Transl Oncol. 2023 Oct;36:101743.
VE-821 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Immunodeficient mice
Hepatocellular carcinoma xenograft model
Intraperitoneal injection
15 mg/kg
Twice a week for 20 days
VE821 significantly inhibited tumor growth in the hepatocellular carcinoma xenograft model without showing significant toxicity
J Exp Clin Cancer Res. 2022 Jan 8;41(1):17.
BALB/c nude mice
Gastric cancer xenograft model
Oral VE-821, intraperitoneal cisplatin
3 mg/kg
Every three days for three weeks
Combination of VE-821 and cisplatin significantly inhibited tumor growth and increased the expression of DNA damage marker γ-H2AX.
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