VE-822
VE-822 is an ATR inhibitor with an IC50 value of 0.019 μM. It is a close analog of VE-821 with a marked increase in potency against ATR.
Radiation (XRT) and chemotherapy induce chromosomal DNA lesions resulting in activation of the ataxia telangiectasiamutated (ATM) and ATM-Rad3-related (ATR) protein kinases in response to double-strand DNA breaks (DSBs) and replication stress, respectively. Defects in the DNA damage response (DDR) such as ATM and p53 deletion/mutation are common in human tumors and occur in up to 70% of patients with PDAC. They might lead to a differential response in DNA repair signaling between normal and tumor cells that could be exploited to increase killing of Radiation (XRT) and chemotherapy induce chromosomal DNA lesions.
In irradiated cancer cells, VE-822 decreased checkpoints of cell-cycle, decreased homologous recombination and increased persistent DNA damage. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity.
Reference:
1.Fokas E, Prevo R, Pollard JR 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.
- 1. Zhengyi Zhen, Yu Chen, et al. "Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation." Nat Commun. 2023 Dec 12;14(1):8217. PMID: 38086852
- 2. Emma E. Croushore, Stacia L. Koppenhafer, et al. "Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress." Cancer Research Communications. AUGUST 17 2023.
- 3. Zhengke Li, Hui Wang-Heaton, et al. "ATR prevents Ca2+ overload-induced necrotic cell death through phosphorylation-mediated inactivation of PARP1 without DNA damage signaling." FASEB J. 2021 May;35(5):e21373. PMID: 33811702
- 4. Kelli L Goss, Stacia L Koppenhafer, et al. "The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors." Oncogene. 2021 Jan;40(3):564-577. PMID: 33191406
- 5. Koppenhafer SL, Goss KL, et al. "mTORC1/2 and protein translation regulate levels of CHK1 and the sensitivity to CHK1 inhibitors in Ewing sarcoma cells." Mol Cancer Ther. 2018 Oct 3. pii: molcanther.0260.2018. PMID: 30282812
- 6. Le TM, Poddar S, Capri JR, et al. "ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways." Nat Commun. 2017 Aug 14;8(1):241. PMID: 28808226
| Storage | Store at -20°C |
| M.Wt | 463.55 |
| Cas No. | 1232416-25-9 |
| Formula | C24H25N5O3S |
| Solubility | ≥50 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH |
| Chemical Name | 3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine |
| SDF | Download SDF |
| 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 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
Pancreatic ductal adenocarcinoma cell (PDAC) |
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Preparation method |
Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
1-2 h |
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Applications |
VE-822 decreases survival of irradiated p53-mutant and K-Ras mutant PDACs. Combination of VE-822 and gemcitabine reduces survival B2–3-fold and significantly more after chemoradiotherapy. In addition, VE-822 increases radation-induced residual gH2AX and 53BP1 foci and decreases Rad51 foci after radiation. |
| Animal experiment [1]: | |
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Animal models |
Female Balb/c nude mice, pancreatic cancer xenografts |
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Dosage form |
Oral gavage, 60 mg/kg |
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Preparation method |
10% Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate |
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Applications |
VE-822 inhibits phospho-Ser-345-Chk1 following treatment of DNA-damaging agents. Combination of VE-822 and radiation significantly prolongs the tumor growth delay compared with the radiation alone. Furthermore, tumor growth delay is substantially longer in the combination group of VE-822+gemcitabine+radiation compared with the combination group of gemcitabine+radiation. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: 1. Fokas E, Prevo R, Pollard JR 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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