Berzosertib (VE-822) hydrochloride is an orally active, CNS-penetrant, and selective ATR kinase inhibitor. Berzosertib hydrochloride blocks ATR kinase activity, abrogates G 2 /M cell cycle checkpoint, impairs DNA damage repair. Berzosertib hydrochloride induces apoptosis, inhibnits conlony migration, inhibits cell proliferation, and activates cGAS-STING axes in cancer cells. Berzosertib hydrochloride can be used for the research of cancers, such as head and neck squamous cell carcinoma, and colorectal cancer [1] [2] [3] [4] [5] [6].
In Vivo, Berzosertib (60 mg/kg; p.o.; daily; 10 days; 1 h before 2 Gy local tumor irradiation) hydrochloride acts synergistically with daily 2 Gy local radiation to delay subcutaneous NSCLC brain metastasis PDX tumor growth in mice[2]. Berzosertib (60 mg/kg; p.o.; daily; 5 days; 1 h before 2.5 Gy whole brain irradiation) hydrochloride combined with daily 2.5 Gy whole brain irradiation significantly improves median overall survival and reduces intracranial tumor growth in mouse NSCLC brain metastasis xenograft model[2]. Berzosertib (60 mg/kg; i.g.; 2 h before Gy IR, then daily for 3 days) hydrochloride produces antitumor efficacy in mouse MC38 and CT26 models, when combined with 5 Gy irradiation and anti-PD-L1[4].
In Vitro, Berzosertib (0.031-1 µM; 72 h) hydrochloride reduces cell viability in Cal-27 and FaDu HNSCC cell lines with IC50 values of 0.285 µM and 0.252 µM, respectively[1]. Berzosertib (0.125-0.5 µM; 24-48 h) hydrochloride inhibits migration in Cal-27 and in FaDu HNSCC cells[1]. Berzosertib (0.25-0.5 µM; 48 h) hydrochloride induces apoptosis in Cal-27 and FaDu cells[1]. Berzosertib (48-72 h) hydrochloride inhibits proliferation of A549, NCI-H226, and NCI-H520 cells with IC50 values in the 1-4 μM range[2]. Berzosertib (40-80 nM; 1 h) hydrochloride enhances radiosensitivity of A549, NCI-H226, and NCI-H520 NSCLC cell lines[2]. Berzosertib (40 nM; 1 h) hydrochloride inhibits radiation-induced ATR (Thr1989) phosphorylation in A549, NCI-H226, and NCI-H520 NSCLC cell lines without affecting ATM (Ser1981) activation[2]. Berzosertib (40 nM; 1 h) hydrochloride abrogates the radiation-induced G2/M cell cycle checkpoint in A549 NSCLC cells, shifting cells into G1 phase[2]. Berzosertib (40-80 nM; 1 h) hydrochloride enhances radiation-induced apoptosis in A549 NSCLC cells when combined with 10 Gy, but not 2 Gy, irradiation[2]. Berzosertib (40 nM; 1 h) hydrochloride inhibits DNA double-strand break repair in A549 cells[2]. Berzosertib (1 µM; 2 h) hydrochloride impairs irradiation-induced G2/M checkpoint initiation and maintenance in HCT116 and CT26 cells, promoting mitotic entry after DNA damage[4]. Berzosertib (1 µM; 2 h) hydrochloride combined with 5 Gy irradiation increases micronuclei formation and cytosolic dsDNA levels in HCT116 and CT26 colorectal cancer cell lines[4]. Berzosertib (1 µM; 2 h) hydrochloride combined with 5 Gy irradiation robustly activates the canonical cGAS-STING-pTBK1/pIRF3 pathway, and upregulates expression of interferon-stimulated genes CXCL10, CCL5, and IFNB in HCT116, SW480, CT26, and MC38 cells[4]. Berzosertib (1 µM; 2 h) hydrochloride combined with 5 Gy irradiation inhibits the recruitment of SHP1 to the TRAF6/STING complex in HCT116 cells, enhancing TRAF6-STING interaction[4].
References:
[1]. Schnoell J, et al. The ATR inhibitor berzosertib acts as a radio- and chemosensitizer in head and neck squamous cell carcinoma cell lines. Invest New Drugs. 2023;41(6):842-850.
[2]. Baschnagel AM, et al. ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts. Mol Cancer Ther. 2021;20(11):2129-2139.
[3]. Fokas E, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012;3(12):e441. Published 2012 Dec 6.
[4]. Liu C, et al. Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer. Cancer Commun (Lond). 2023;43(4):435-454.
[5]. Gorainow N, et al. Berzosertib enhances the sensitivity of pediatric diffuse midline glioma H3K27-altered cells to radiotherapy. Cell Death Dis. 2026;17(1):331. Published 2026 Mar 20.
[6]. Kurmasheva RT, et al. Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2018;65(2):10.1002/pbc.26825.
In Vivo, Berzosertib (60 mg/kg; p.o.; daily; 10 days; 1 h before 2 Gy local tumor irradiation) hydrochloride acts synergistically with daily 2 Gy local radiation to delay subcutaneous NSCLC brain metastasis PDX tumor growth in mice[2]. Berzosertib (60 mg/kg; p.o.; daily; 5 days; 1 h before 2.5 Gy whole brain irradiation) hydrochloride combined with daily 2.5 Gy whole brain irradiation significantly improves median overall survival and reduces intracranial tumor growth in mouse NSCLC brain metastasis xenograft model[2]. Berzosertib (60 mg/kg; i.g.; 2 h before Gy IR, then daily for 3 days) hydrochloride produces antitumor efficacy in mouse MC38 and CT26 models, when combined with 5 Gy irradiation and anti-PD-L1[4].
In Vitro, Berzosertib (0.031-1 µM; 72 h) hydrochloride reduces cell viability in Cal-27 and FaDu HNSCC cell lines with IC50 values of 0.285 µM and 0.252 µM, respectively[1]. Berzosertib (0.125-0.5 µM; 24-48 h) hydrochloride inhibits migration in Cal-27 and in FaDu HNSCC cells[1]. Berzosertib (0.25-0.5 µM; 48 h) hydrochloride induces apoptosis in Cal-27 and FaDu cells[1]. Berzosertib (48-72 h) hydrochloride inhibits proliferation of A549, NCI-H226, and NCI-H520 cells with IC50 values in the 1-4 μM range[2]. Berzosertib (40-80 nM; 1 h) hydrochloride enhances radiosensitivity of A549, NCI-H226, and NCI-H520 NSCLC cell lines[2]. Berzosertib (40 nM; 1 h) hydrochloride inhibits radiation-induced ATR (Thr1989) phosphorylation in A549, NCI-H226, and NCI-H520 NSCLC cell lines without affecting ATM (Ser1981) activation[2]. Berzosertib (40 nM; 1 h) hydrochloride abrogates the radiation-induced G2/M cell cycle checkpoint in A549 NSCLC cells, shifting cells into G1 phase[2]. Berzosertib (40-80 nM; 1 h) hydrochloride enhances radiation-induced apoptosis in A549 NSCLC cells when combined with 10 Gy, but not 2 Gy, irradiation[2]. Berzosertib (40 nM; 1 h) hydrochloride inhibits DNA double-strand break repair in A549 cells[2]. Berzosertib (1 µM; 2 h) hydrochloride impairs irradiation-induced G2/M checkpoint initiation and maintenance in HCT116 and CT26 cells, promoting mitotic entry after DNA damage[4]. Berzosertib (1 µM; 2 h) hydrochloride combined with 5 Gy irradiation increases micronuclei formation and cytosolic dsDNA levels in HCT116 and CT26 colorectal cancer cell lines[4]. Berzosertib (1 µM; 2 h) hydrochloride combined with 5 Gy irradiation robustly activates the canonical cGAS-STING-pTBK1/pIRF3 pathway, and upregulates expression of interferon-stimulated genes CXCL10, CCL5, and IFNB in HCT116, SW480, CT26, and MC38 cells[4]. Berzosertib (1 µM; 2 h) hydrochloride combined with 5 Gy irradiation inhibits the recruitment of SHP1 to the TRAF6/STING complex in HCT116 cells, enhancing TRAF6-STING interaction[4].
References:
[1]. Schnoell J, et al. The ATR inhibitor berzosertib acts as a radio- and chemosensitizer in head and neck squamous cell carcinoma cell lines. Invest New Drugs. 2023;41(6):842-850.
[2]. Baschnagel AM, et al. ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts. Mol Cancer Ther. 2021;20(11):2129-2139.
[3]. Fokas E, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012;3(12):e441. Published 2012 Dec 6.
[4]. Liu C, et al. Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer. Cancer Commun (Lond). 2023;43(4):435-454.
[5]. Gorainow N, et al. Berzosertib enhances the sensitivity of pediatric diffuse midline glioma H3K27-altered cells to radiotherapy. Cell Death Dis. 2026;17(1):331. Published 2026 Mar 20.
[6]. Kurmasheva RT, et al. Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2018;65(2):10.1002/pbc.26825.