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]。