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/贝索塞替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
human gastric cancer organoids
10 μM
48 h
To test the effect of Berzosertib on the viability of ARID1A wild-type and mutant human gastric cancer organoids, results showed that Berzosertib selectively reduced the viability of ARID1A mutant organoids.
Sci Adv. 2024 Mar 15;10(11):eadh4435.
DMS 114
1 µM
6 or 24 h
Berzosertib specifically inhibited the activation of ATR and its downstream target CHK1, with less notable effects on other DNA damage repair pathways, leading to continued cell cycle progression and ultimately mitotic catastrophe and cell death.
EMBO Mol Med. 2023 Aug 7;15(8):e17313.
A549 cells
1 µM
72 h
Pre-treatment with Berzosertib significantly increased the radiosensitivity of A549 cells, reducing the radioresistance of shScr cells to the level of shSTX18 cells.
Cell Death Dis. 2022 Jun 6;13(6):529.
H460 cells
1 µM
72 h
Pre-treatment with Berzosertib significantly increased the radiosensitivity of H460 cells, and H460 cells were intrinsically more sensitive to Berzosertib.
Cell Death Dis. 2022 Jun 6;13(6):529.
PDOVCs#3 cells
80 nM
1 h
Berzosertib in combination with CDDP significantly increased DNA damage in PDOVCs#3 and PDOVCs#4, reversing DDUP-mediated DNA damage repair.
Cell Death Dis. 2023 Aug 26;14(8):568.
PDOVCs#4 cells
80 nM
1 h
Berzosertib in combination with CDDP significantly increased DNA damage in PDOVCs#3 and PDOVCs#4, reversing DDUP-mediated DNA damage repair.
Cell Death Dis. 2023 Aug 26;14(8):568.
Huh7 cells
5 μM
48 h
To evaluate the cytotoxic and DNA damage effects of Berzosertib on Huh7 cells
Hepatology. 2023 Nov 1;78(5):1462-1477.
Berzosertib/贝索塞替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
LMS33 PDX model
Oral
60 mg/kg
5 days per week for 21 days
To evaluate the antitumor activity of the ATR inhibitor Berzosertib in the LMS33 PDX model. Results showed that tumor growth was not significantly decreased over the 21-day treatment period, indicating the lack of activity of this drug as monotherapy in this model.
In the PDX-06 model, lurbinectedin alone almost completely inhibited tumor growth, and the addition of berzosertib did not significantly improve efficacy. However, berzosertib cotreatment significantly reduced p-CHK1 activation, indicating target engagement.
EMBO Mol Med. 2023 Aug 7;15(8):e17313.
Mouse
PDX-06
Intravenous and intraperitoneal
20 mg/kg
Every 7 days for 4 cycles
Assess the in vivo synergy of Berzosertib with Lurbinectedin
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