VE-821

ATR kinase inhibitor CAS# 1232410-49-9

VE-821

Catalog No. BCC1207----Order now to get a substantial discount!

Product Name & Size Price Stock
VE-821:10mg $87.00 In stock
VE-821:20mg $148.00 In stock
VE-821:50mg $348.00 In stock
VE-821:100mg $609.00 In stock
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Chemical structure

VE-821

3D structure

Chemical Properties of VE-821

Cas No. 1232410-49-9 SDF Download SDF
PubChem ID 51000408 Appearance Powder
Formula C18H16N4O3S M.Wt 368.41
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (135.72 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide
SMILES CS(=O)(=O)C1=CC=C(C=C1)C2=CN=C(C(=N2)C(=O)NC3=CC=CC=C3)N
Standard InChIKey DUIHHZKTCSNTGM-UHFFFAOYSA-N
Standard InChI InChI=1S/C18H16N4O3S/c1-26(24,25)14-9-7-12(8-10-14)15-11-20-17(19)16(22-15)18(23)21-13-5-3-2-4-6-13/h2-11H,1H3,(H2,19,20)(H,21,23)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of VE-821

DescriptionVE-821 is a potent and selective ATP competitive inhibitor of ATR with Ki/IC50 of 13 nM/26 nM.
TargetsATR    
IC5013 nM/26 nM (Ki/IC50)     

Protocol

Kinase experiment [1]:

Inhibitory activities

VE-821 (2 μM) was screened against the indicated human (h), rat (r), mouse (m) and fission yeast (y) kinases using the Millipore KinaseProfiler service, at ATP concentrations equal to each enzyme’s ATP Km.

Cell experiment [1]:

Cell lines

HFL1 cells; HCT116 cancer cells; H23 cancer cell line.

Preparation method

The solubility of this compound in DMSO is >10 mM. 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.

Reacting condition

10 μM; 24, 48 or 96 h.

Applications

HFL1 cells were pretreated with 10 μM VE-821 or DMSO before addition of 200 μM cisplatin (Cis), 1 μM gemcitabine (Gem), 100 μM etoposide (Etop) or 5 Gy ionizing radiation (IR), VE-821 blocks Chk1 Ser345 phosphorylation under all conditions and inhibits H2AX phosphorylation in treatment with cisplatin and gemcitabine. In the H23 cancer cell line, VE-821 shows marked synergy with cisplatin in growth arrest.

References:

[1]. Reaper PM1, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA, Golec JM, Pollard JR. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol, 2011, 7(7): 428-430.

VE-821 Dilution Calculator

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VE-821 Molarity Calculator

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Preparing Stock Solutions of VE-821

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.7144 mL 13.5718 mL 27.1437 mL 54.2873 mL 67.8592 mL
5 mM 0.5429 mL 2.7144 mL 5.4287 mL 10.8575 mL 13.5718 mL
10 mM 0.2714 mL 1.3572 mL 2.7144 mL 5.4287 mL 6.7859 mL
50 mM 0.0543 mL 0.2714 mL 0.5429 mL 1.0857 mL 1.3572 mL
100 mM 0.0271 mL 0.1357 mL 0.2714 mL 0.5429 mL 0.6786 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of VE-821

1. 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. doi: 10.4161/cbt.21093. Epub 2012 Jul 24.
Abstract
The ATR inhibitor VE-821 significantly sensitized a few pancreatic cancer cells to DNA damaging agents, radiotherapy and gemcitabine, where IT inhibited Chk1 phosphorylation and homologous recombination repair, triggered inhibition of G 2/M arrest, reduced radiosurvival and increased DNA damage in radiation- and gemcitabine-treated cancer cells.
2. Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukaemia (HL-60). Radiat Environ Biophys. 2013 Nov;52(4):471-9. doi: 10.1007/s00411-013-0486-5. Epub 2013 Aug 11.
Abstract
The ATR inhibitor VE-821 exerted a more pronounced radiosenstizing effect in HL-60 cells, where it reduced phosphorylation of check-point kinase 1 and the repair of the radiation damage, inhibited G2 cell cycle arrest and induced apoptosis.

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Background on VE-821

VE-821 is a potent, highly-selective, and ATP-competitive DNA damage response (DDR) kinase ATR inhibitor with Ki value of 13nM. VE-821 specifically inhibits ATR, revealing low cross-reactivity against the mammalian target of rapamycin (mTOR), DNA-dependent protein kinase (DNA-PK), phosphoinositol 3-kinase-γ (PI3K) and the related PIKKs ATM [1].

HL-60 cells treated with VE-821 (10μM) showed reduction of phosphorylatin of Chk1 (Ser 345), inhibition of cell growth, and a radiosensitizing effect after Gamma-ray irradiation [2].

VE-821 has also been demonstrated to down-regulate the phosphorylated Chk1 (Ser 345) but it does not inhibit the phosphorylation of Chk2 (Thr68) and ATM (Ser1981) in pancreatic cancer cell lines, including PSN-1 and MiaPaCa-2 cells that are treated with gemcitabine or radiation. VE-821 combined with gemcitabine (a nucleoside analog) has caused a remarkable increase of cytotoxic effect of gemcitabine against hypoxia [3].

References:
[1] Reaper PM1, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA, Golec JM, Pollard JR. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011 Apr 13;7(7):428-30.
[2] Vávrová J1, Zárybnická L, Lukášová E, Řezáčová M, Novotná E, Sinkorová Z, Tichý A, Pejchal J, Durišová K. Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukaemia (HL-60). Radiat Environ Biophys. 2013 Nov;52(4):471-9.
[3] Prevo R1, Fokas E, Reaper PM, Charlton PA, Pollard JR, McKenna WG, Muschel RJ, Brunner TB.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.

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References on VE-821

Radiosensitization of human leukemic HL-60 cells by ATR kinase inhibitor (VE-821): phosphoproteomic analysis.[Pubmed:25003641]

Int J Mol Sci. 2014 Jul 7;15(7):12007-26.

DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)-triggered by radiation-induced double strand breaks-is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells.

Synergistic potentiation of (-)-lomaiviticin A cytotoxicity by the ATR inhibitor VE-821.[Pubmed:27177826]

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3122-3126.

(-)-Lomaiviticin A (1) is a cytotoxic bacterial metabolite that induces double-strand breaks in DNA. Here we show that the cytotoxicity of (-)-lomaiviticin A (1) is synergistically potentiated in the presence of VE-821 (7), an inhibitor of ataxia telangiectasia and Rad3-related protein (ATR). While 0.5nM 1 or 10muM 7 alone are non-lethal to K562 cells, co-incubation of the two leads to high levels of cell kill (81% and 94% after 24 and 48h, respectively). Mechanistic data indicate that cells treated with 1 and 7 suffer extensive DNA double-strand breaks and apoptosis. These data suggest combinations of 1 and 7 may be a valuable chemotherapeutic strategy.

VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation.[Pubmed:26286029]

Radiat Oncol. 2015 Aug 19;10:175.

BACKGROUND: High linear energy transfer (LET) radiation such as carbon ion particles is successfully used for treatment of solid tumors. The reason why high LET radiation accomplishes greater tumor-killing than X-rays is still not completely understood. One factor would be the clustered or complex-type DNA damages. We previously reported that complex DNA double-strand breaks produced by high LET radiation enhanced DNA end resection, and this could lead to higher kinase activity of ATR protein recruited to RPA-coated single-stranded DNA. Although the effect of ATR inhibition on cells exposed to low LET gamma-rays has recently been reported, little is known regarding the effect of ATR inhibitor on cells treated with high LET radiation. The purpose of this study is to investigate the effects of the ATR inhibitor VE-821 in human tumor and normal cells irradiated with high LET carbon ions. FINDINGS: HeLa, U2OS, and 1BR-hTERT (normal) cells were pre-treated with 1 muM VE-821 for 1 hour and irradiated with either high LET carbon ions or X-rays. Cell survival, cell cycle distribution, cell growth, and micronuclei formation were evaluated. VE-821 caused abrogation of G2/M checkpoint and forced irradiated cells to divide into daughter cells. We also found that carbon ions caused a higher number of multiple micronuclei than X-rays, leading to decreased cell survival in tumor cells when treated with VE-821, while the survival of irradiated normal cells were not significantly affected by this inhibitor. CONCLUSIONS: ATR inhibitor would be an effective tumor radiosensitizer with carbon ion irradiation.

ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses.[Pubmed:25269479]

Cancer Res. 2014 Dec 1;74(23):6968-79.

Camptothecin and its derivatives, topotecan and irinotecan, are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, and the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop novel drug combinations, we conducted a synthetic lethal siRNA screen using a library that targets nearly 7,000 human genes. Depletion of ATR, the main transducer of replication stress, came as a top candidate gene for camptothecin synthetic lethality. Validation studies using ATR siRNA and the ATR inhibitor VE-821 confirmed marked antiproliferative synergy with camptothecin and even greater synergy with LMP-400. Single-cell analyses and DNA fiber combing assays showed that VE-821 abrogates the S-phase replication elongation checkpoint and the replication origin-firing checkpoint induced by camptothecin and LMP-400. As expected, the combination of Top1 inhibitors with VE-821 inhibited the phosphorylation of ATR and Chk1; however, it strongly induced gammaH2AX. In cells treated with the combination, the gammaH2AX pattern changed over time from the well-defined Top1-induced damage foci to an intense peripheral and diffuse nuclear staining, which could be used as response biomarker. Finally, the clinical derivative of VE-821, VX-970, enhanced the in vivo tumor response to irinotecan without additional toxicity. A key implication of our work is the mechanistic rationale and proof of principle it provides to evaluate the combination of Top1 inhibitors with ATR inhibitors in clinical trials.

Description

VE-821 is a potent ATP-competitive inhibitor of ATR with Ki/IC50 of 13 nM/26 nM.

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