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VE-821

Catalog No. T3032   CAS 1232410-49-9
Synonyms: ATR Inhibitor IV

VE-821 (ATR Inhibitor IV) is a selective ATP competitive inhibitor of ATR( Ki/IC50: 13/26 nM in cell-free assays).

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VE-821 Chemical Structure
VE-821, CAS 1232410-49-9
Pack Size Availability Price/USD Quantity
2 mg In stock $ 30.00
5 mg In stock $ 46.00
10 mg In stock $ 72.00
25 mg In stock $ 126.00
50 mg In stock $ 198.00
100 mg In stock $ 369.00
1 mL * 10 mM (in DMSO) In stock $ 51.00
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Purity: 99.97%
Purity: 99.26%
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Biological Description
Chemical Properties
Storage & Solubility Information
Description VE-821 (ATR Inhibitor IV) is a selective ATP competitive inhibitor of ATR( Ki/IC50: 13/26 nM in cell-free assays).
Targets&IC50 ATR:13 nM (Ki, cell free)
In vitro VE-821 shows excellent selectivity for ATR with minimal cross-reactivity against the related PIKKs ATM, DNA-dependent protein kinase (DNA-PK), mammalian target of rapamycin and phosphoinositol 3-kinase-γ (Kis of 16 μM, 2.2 μM, >1 μM and 3.9 μM, respectively). VE-821 blocked H2AX phosphorylation in hydroxyurea-treated HT29 cancer cells and had no impact on the M059J or HT144 lines treated with neocarzinostatin [1]. VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells [2]. VE-821 (1 and 4 μM) enhanced H2AX phosphorylation on Ser139 induced by topotecan, and cisplatin in OVCAR-8 cells. VE-821 did not block ATR-mediated Ser345 Chk1 or Ser296 autophosphorylation triggered by gemcitabine, topotecan, or cisplatin [3].
Kinase Assay The ability of compounds (e.g., VE-821) to inhibit ATR, ATM or DNAPK kinase activity is tested using a radiometric-phosphate incorporation assay. A stock solution is prepared consisting of the appropriate buffer, kinase, and target peptide. To this is added the compound of interest, at varying concentrations in DMSO to a final DMSO concentration of 7%. Assays are initiated by addition of an appropriate [g-33P]ATP solution and incubated at 25°C. Assays are stopped, after the desired time course, by addition of phosphoric acid and ATP to a final concentration of 100 mM and 0.66 μM, respectively. Peptides are captured on a phosphocellulose membrane, prepared, and washed six times with 200 μL of 100 mM phosphoric acid, prior to the addition of 100 μL of scintillation cocktail and scintillation counting on a 1450 Microbeta Liquid Scintillation Counter. Dose-response data are analyzed using GraphPad Prism software [4].
Cell Research Clonogenic survival assays were performed as described before. Briefly, logarithmically growing cells were plated in triplicate in 6-well tissue culture dishes under oxic (21% O2) or hypoxic conditions (0.5% O2) using an InVivo2 300 chamber. Cells were incubated for 6 h before irradiation under oxia or hypoxia using tightly sealed chambers. The target O2 level was achieved within 6 h of gassing and maintained during irradiation, as confirmed by an OxyLite oxygen probe. Cells irradiated under hypoxia were exposed to normoxia at 1 h post-irradiation. As standard, VE-821 (1 μM) was added 1 h prior to irradiation (6 Gy) and was washed away 72 h after irradiation. For the chemotherapy experiments, cells were initially exposed to increasing concentrations of gemcitabine (5, 10 and 20 nM) for 24 h before addition of the VE-821 (1 μM) for another 72 h. The effect of triple combination of irradiation with VE-821 and gemcitabine was examined as well. Cells were incubated for 10–21 d until colonies were stained with 0.5% crystal violet and counted in a CellCount automated colony counter. Clonogenic survival was calculated and data were fitted in GraphPad Prism 4.0 [2].
Synonyms ATR Inhibitor IV
Molecular Weight 368.41
Formula C18H16N4O3S
CAS No. 1232410-49-9

Storage

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

Solubility Information

DMSO: 69 mg/mL (187.3 mM)

Ethanol: < 1 mg/mL (insoluble or slightly soluble)

TargetMolReferences and Literature

1. Reaper PM, et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011 Apr 13;7(7):428-30. 2. Prevo R, et al. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012 Sep;13(11):1072-81. 3. Huntoon CJ, et al. ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res. 2013 Jun 15;73(12):3683-91. 4. Charrier JD, et al. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011 Apr 14;54(7):2320-30. 5. Flach J, Jann J C, Knaflic A, et al. Replication stress signaling is a therapeutic target in myelodysplastic syndromes with splicing factor mutations[J]. Haematologica. 2020 6. Weizhe Li, Hong-Yan Wang, Xiaolu Zhao, Hongguo Duan, Binghua Cheng, Yafei Liu, Mengjie Zhao et al. A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair [J]. Science Advances. 2019 Mar 6;5(3):eaau7566. 7. Bai Y, Wang W, Li S, et al. C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex[J]. Molecular Cell. 2019.

TargetMolCitations

1. Bai Y, Wang W, Li S, et al. C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex. Molecular Cell. 2019 2. Li W, Wang H Y, Zhao X, et al. A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair. Science Advances. 2019, 5(3): eaau7566 3. Flach J, Jann J C, Knaflic A, et al. Replication stress signaling is a therapeutic target in myelodysplastic syndromes with splicing factor mutations. Haematologica. 2021 Nov 1;106(11):2906-2917

Related compound libraries

This product is contained In the following compound libraries:
Anti-Cancer Active Compound Library Inhibitor Library Bioactive Compound Library Metabolism Compound Library Target-Focused Phenotypic Screening Library Anti-Aging Compound Library NO PAINS Compound Library Cancer Cell Differentiation Compound Library Neural Regeneration Compound Library Anti-Breast Cancer Compound Library

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Keywords

VE-821 1232410-49-9 DNA Damage/DNA Repair PI3K/Akt/mTOR signaling ATM/ATR ATM and RAD3 related VE 821 Inhibitor Ataxia telangiectasia mutated inhibit ATR Inhibitor IV VE821 inhibitor

 

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