Berzosertib

• CAT Number: I000916
• CAS Number: 1232416-25-9
• Molecular Formula: C24H25N5O3S
• Molecular Weight: 463.55
• Purity: ≥95%
• Synonyms: 3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine
• InChI: InChI=1S/C24H25N5O3S/c1-15(2)33(30,31)19-10-8-18(9-11-19)21-14-27-24(25)23(28-21)22-12-20(29-32-22)17-6-4-16(5-7-17)13-26-3/h4-12,14-15,26H,13H2,1-3H3,(H2,25,27)
• InChIKey: JZCWLJDSIRUGIN-UHFFFAOYSA-N
• 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

Berzosertib (VE-822) is an ATR inhibitor with a Ki value of less than 0.2 nM. It also inhibits ATM with a Ki of 34 nM.
Berzosertib (VE-822) also inhibits DNK-PA, mTOR, PI3Kγ with IC50 of >4, >1, and 0.22 μM, respectively. In PSN-1 and MiaPaCa-2 cells, Berzosertib (VE-822) inhibits ATR and ATM with IC50 of 19 nM and 2.6 μM, respectively. VE-822 (80 nM) reduces phospho-Ser345-Chk1 after NSC 613327 (100 nM), radiation (XRT) (6 Gy) or both in PDAC. Additionally, Berzosertib (VE-822) does not inhibit ATM, Chk2 or DNA-PK phosphorylation in response to radiation, which further supports the selectivity of Berzosertib (VE-822) for ATR. VE-822 decreases survival of irradiated PDAC (all lines used are p53-mutant; K-Ras mutant). Knock down of Chk1 by siRNA sensitizes PSN-1 and MiaPaCa-2 cells to radiation but the radiosensitising effect is less profound compare with Berzosertib (VE-822). Adding Berzosertib (VE-822) to NSC 613327 reduces survival ~2-3-fold and dramatically more after chemoradiotherapy[1].
PSN-1 xenografts are treated with Berzosertib (VE-822) (60 mk/kg; d0, 1), NSC 613327 (100 mg/kg; d0) and/or XRT (6 Gy; d1). Tumors are then harvested 2 h post-XRT. Berzosertib (VE-822) inhibits p-Ser-345-Chk1 in xenografts after DNA-damaging agents, establishing VE-822 as a potent inhibitor of ATR in vivo. Besides, Berzosertib (VE-822) enhances the therapeutic efficacy of radiation (XRT) in MiaPaCa-2 and PSN-1 xenograft models[1].

Reference

[1]. 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 Dec 6;3:e441.
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