Berzosertib (VE-822)是一种静脉给药的、高度强效且选择性的ATR抑制剂(IC50=19nM)。
Cas No.:1232416-25-9
Sample solution is provided at 25 µL, 10mM.
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Berzosertib (VE-822) is an intravenous (i.v.), highly potent and selective inhibitor of ATR (IC50 =19nM) [1]. Under radiation, Berzosertib can activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STING-p65 axis, via promoting SUMOylation of SHP1 at lysine 127 [2]. Berzosertib has been widely used to inhibit tumor progression and enhance the killing effect of radiation therapy on tumors[3].
In vitro, Berzosertib treatment for 72h significantly inhibited the viability of Cal-27 and FaDu cells with IC50 values of 0.285µM and 0.252µM, respectively[4]. Treatment with 80nM Berzosertib for 19 hours significantly reduced the phosphorylation level of Chk1 and decreased the survival of MiaPaCa-2 cells under 4Gy radiation[5]. Treatment with 6µM Berzosertib for 24 hours led to a significant increase in the levels of γ-H2AX, pp53, and cc3 in U2OS cells, accompanied by DNA breaks and cell apoptosis[6].
In vivo, Berzosertib treatment via a single oral dose of 60mg/kg for 48 hours led to the accumulation of DNA damage and a decrease in P-Chk1 expression within the tumors of mice bearing the OD26749 xenografts [7]. Administering 60mg/kg of Berzosertib orally 4 times per week for 3 weeks significantly inhibited tumor growth in H827-xenograft mice and upregulated the activity of OTUD1 protein[8].
References:
[1] Middleton M R, Dean E, Evans T R J, et al. Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine±cisplatin in patients with advanced solid tumours[J]. British Journal of Cancer, 2021, 125(4): 510-519.
[2] Liu C, Wang X, Qin W, et al. Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer[J]. Cancer Communications, 2023, 43(4): 435-454.
[3] Wang L W, Jiang S, Yuan Y H, et al. Recent advances in synergistic antitumor effects exploited from the inhibition of ataxia telangiectasia and RAD3-related protein kinase (ATR)[J]. Molecules, 2022, 27(8): 2491.
[4] Schnoell J, Sparr C, Al-Gboore S, et al. The ATR inhibitor berzosertib acts as a radio-and chemosensitizer in head and neck squamous cell carcinoma cell lines[J]. Investigational New Drugs, 2023, 41(6): 842-850.
[5] Fokas E, Prevo R, Pollard J R, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation[J]. Cell death & disease, 2012, 3(12): e441-e441.
[6] Yin Q, Liu X, Hu L, et al. VE-822, a novel DNA Holliday junction stabilizer, inhibits homologous recombination repair and triggers DNA damage response in osteogenic sarcomas[J]. Biochemical pharmacology, 2021, 193: 114767.
[7] Hall A B, Newsome D, Wang Y, et al. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970[J]. Oncotarget, 2014, 5(14): 5674.
[8] Zhang Q, Li J, Chen Z, et al. VE-822 upregulates the deubiquitinase OTUD1 to stabilize FHL1 to inhibit the progression of lung adenocarcinoma[J]. Cellular Oncology, 2023, 46(4): 1001-1014.
Berzosertib (VE-822)是一种静脉给药的、高度强效且选择性的ATR抑制剂(IC50=19nM) [1]。在辐射作用下，Berzosertib一方面通过增加胞质双链DNA水平激活经典的cGAS-STING-pTBK1/pIRF3轴，另一方面通过促进SHP1在赖氨酸127位点的SUMO化修饰，削弱SHP1介导的TRAF6-STING-p65轴抑制，从而激活非经典的STING信号通路[2]。Berzosertib已被广泛用于抑制肿瘤进展，并增强放射治疗对肿瘤的杀伤作用[3]。
在体外，Berzosertib处理Cal-27和FaDu细胞72小时，显著抑制了细胞活力，IC50值分别为0.285µM和0.252µM[4]。80nM的Berzosertib处理MiaPaCa-2细胞19小时，在4Gy辐射下显著降低了Chk1的磷酸化水平并降低了细胞存活率[5]。6µM的Berzosertib处理U2OS细胞24小时，导致γ-H2AX、pp53和cc3水平显著升高，并伴随DNA断裂和细胞凋亡[6]。
在体内，单次口服60mg/kg剂量的Berzosertib，作用48小时，导致携带OD26749异种移植瘤的小鼠肿瘤内DNA损伤积累和P-Chk1表达下降[7]。每周口服4次60mg/kg剂量Berzosertib，持续3周，显著抑制了H827异种移植小鼠的肿瘤生长，并上调了OTUD1蛋白的活性[8]。
| Cell experiment [1]: | |
Cell lines | Cal-27 cells |
Preparation Method | Cal-27 cells were grown in DMEM with 10% (v/v) fetal bovine serum (FBS), antibiotic/antimycotic solution at 37°C in 5% CO2/atmosphere. Cal-27 cells were cultured in growth medium in 96-well dishes at a density of 5000 cells per well. One day after seeding, cells were treated with Berzosertib (0.031, 0.063, 0.125, 0.25, and 0.5µM). After 72h of incubation, cell viability was measured. |
Reaction Conditions | 0.031, 0.063, 0.125, 0.25, and 0.5µM; 72h |
Applications | Berzosertib treatment significantly inhibited the cell viability of Cal-27 cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | BALB/c nude mice |
Preparation Method | Male BALB/c nude mice (4 weeks old) were housed singly in a standard environment with food and water ad libitum. H827 cells (5×106) were suspended in 200µl PBS and then injected subcutaneously into the left and right. Two weeks after tumors became measurable, mice were randomly divided into PBS-treatment and Berzosertib treatment groups. Berzosertib was administered at a dose of 60mg/kg in 5% DMSO + 45% PEG300 + 50% sterile PBS once per day for 4 consecutive days every week by oral gavage and lasted 3 weeks. Tumor volume was measured and tumor volume=0.5×length×width2. |
Dosage form | 60mg/kg; 4 times a week for 3 weeks; p.o. |
Applications | Berzosertib treatment significantly inhibited tumor growth in the H827 xenograft mouse model. |
References: | |
| Cas No. | 1232416-25-9 | SDF | |
| 化学名 | 3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine | ||
| Canonical SMILES | CC(C)S(=O)(=O)C1=CC=C(C=C1)C2=CN=C(C(=N2)C3=CC(=NO3)C4=CC=C(C=C4)CNC)N | ||
| 分子式 | C24H25N5O3S | 分子量 | 463.55 |
| 溶解度 | ≥ 50mg/mL in DMSO | 储存条件 | Store at -20° C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1573 mL | 10.7863 mL | 21.5726 mL |
| 5 mM | 431.5 μL | 2.1573 mL | 4.3145 mL |
| 10 mM | 215.7 μL | 1.0786 mL | 2.1573 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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