ETP-46464

ATR inhibitor,potent and selective CAS# 1345675-02-6

ETP-46464

Catalog No. BCC3913----Order now to get a substantial discount!

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Chemical structure

ETP-46464

3D structure

Chemical Properties of ETP-46464

Cas No. 1345675-02-6 SDF Download SDF
PubChem ID 72199292 Appearance Powder
Formula C30H22N4O2 M.Wt 470.52
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble in DMSO > 10 mM
Chemical Name 2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1,3]oxazino[5,4-c]quinolin-1-yl)phenyl]propanenitrile
SMILES CC(C)(C#N)C1=CC=C(C=C1)N2C3=C4C=C(C=CC4=NC=C3COC2=O)C5=CC6=CC=CC=C6N=C5
Standard InChIKey DPLMXAYKJZOTKO-UHFFFAOYSA-N
Standard InChI InChI=1S/C30H22N4O2/c1-30(2,18-31)23-8-10-24(11-9-23)34-28-22(17-36-29(34)35)16-33-27-12-7-19(14-25(27)28)21-13-20-5-3-4-6-26(20)32-15-21/h3-16H,17H2,1-2H3
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 ETP-46464

DescriptionETP-46464 is a potent and selective inhibitor of ATR with an IC50 value of 25 nM.
TargetsmTORATRDNA-PKPI3KαATM  
IC500.6 nM14 nM36 nM170 nM545 nM  

Protocol

Kinase Assay [1]
Compounds (e.g., ETP-46464) and control inhibitors are delivered directly to cell media (100 μL per well) with a multi-well pipette at a final concentration of 10 μM. Media content is homogenized by carefully vortexing plates at 500 rpm. Prior to 4-hydroxy-tamoxifen (4-OHT) addition, Compounds (e.g., ETP-46464 ) are incubated at 37ºC for 15 minutes. Next, to induce ATR activity, 4-OHT is added to all wells and incubated for 60 minutes at 37ºC. Finally, cells are fixed with paraformaldehyde and processed for IF. Every compound (e.g., ETP-46464) is analyzed at least in three independent experiments[1].

Cell Assay [2]
Cells are trypsinized with 0.25% Trypsin-EDTA and counted with 0.4% Trypan Blue using an automated cell counter and plated in 96-well plates at 5000 cells per well for KLE, HEC1B and HELA and 10,000 cells per well for OVCAR3, A2780, A2780-CP20 and SIHA. After cells attach and reach approximately 60% confluency (24-48 h post seeding), media is removed and replaced with fresh media containing Cisplatin (0, 0.78, 1.56, 3.13, 6.25, 12.5, 25 or 50 µM) or Carboplatin (0, 1.56, 3.13, 6.25, 12.5, 25, 50 or 100 µM) in 0.15% DMSO, 5 µM ETP-46464, 10 µM KU55933, or a combination of 5 µM ETP-46464 and 10 µM KU55933 and incubated for 72 h. Final concentrations of ETP-46464 and KU55933 utilized are based on prior evidence indicating inhibition of ATR and ATM signaling, respectively. Single-agent dose response analyses of ETP-46464 and KU55933 in a subset of cell lines revealed a wide LD50 range (10.0±8.7 and 38.3±7.6 µM, respectively). Similarly, cells are treated with fresh media containing Cisplatin (0, 0.78, 1.56, 3.13, 6.25, 12.5, 25 or 50 µM) in 0.08% DMSO and 5 µM VE-821. Cell viability is assessed using the MTS CellTiter 96 Aqueous One Solution Cell Proliferation Assay. After a 2 h incubation at 37°C, absorbance is measured at 490 nm using a microplate spectrophotometer. Three biological replicates are performed for each cell line where each inhibitor(s)/Cisplatin concentration is assayed in triplicate for each experiment[2].

References:
[1]. Toledo LI, et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol. 2011 Jun;18(6):721-7. [2]. Teng PN, et al. Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells. Gynecol Oncol. 2015 Mar;136(3):554-61.

ETP-46464 Dilution Calculator

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ETP-46464 Molarity Calculator

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Preparing Stock Solutions of ETP-46464

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1253 mL 10.6265 mL 21.2531 mL 42.5062 mL 53.1327 mL
5 mM 0.4251 mL 2.1253 mL 4.2506 mL 8.5012 mL 10.6265 mL
10 mM 0.2125 mL 1.0627 mL 2.1253 mL 4.2506 mL 5.3133 mL
50 mM 0.0425 mL 0.2125 mL 0.4251 mL 0.8501 mL 1.0627 mL
100 mM 0.0213 mL 0.1063 mL 0.2125 mL 0.4251 mL 0.5313 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.

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Background on ETP-46464

ETP-46464 is a potent and selective inhibitor for ATR (IC50 = 25 nM).

ATR (ATM- and Rad3-related) is a member of PIKK (phosphatidylinositol 3-kinase-like kinases) that regulates the DNA damage response pathways. It is a DNA damage sensor that is activated upon genotoxic stresses (e.g. ionizing radiation, UV radiation and DNA replication stalling) and phosphorylates its downstream substrates (e.g. p53, BRCA1 and CHEK1).

ETP-46464 abolished the G2/M checkpoint. It caused the presence of micronuclei or completely fragmented nuclei in cells under ionizing radiation. Cells treated simultaneously with hydroxyurea and ETP-46464 exhibited elevated ATM and Chk2 phosphorylation. In U2OS cells, ETP-46464 promoted the breakage of stalked replication forks. [1]

Reference:
1. Toledo LI, Murga M, Zur R et al.  A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol. 2011 Jun;18(6):721-7.

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References on ETP-46464

A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations.[Pubmed:21552262]

Nat Struct Mol Biol. 2011 Jun;18(6):721-7.

Oncogene activation has been shown to generate replication-born DNA damage, also known as replicative stress. The primary responder to replicative stress is not Ataxia-Telangiectasia Mutated (ATM) but rather the kinase ATM and Rad3-related (ATR). One limitation for the study of ATR is the lack of potent inhibitors. We here describe a cell-based screening strategy that has allowed us to identify compounds with ATR inhibitory activity in the nanomolar range. Pharmacological inhibition of ATR generates replicative stress, leading to chromosomal breakage in the presence of conditions that stall replication forks. Moreover, ATR inhibition is particularly toxic for p53-deficient cells, this toxicity being exacerbated by replicative stress-generating conditions such as the overexpression of cyclin E. Notably, one of the compounds we identified is NVP-BEZ235, a dual phosphatidylinositol-3-OH kinase (PI3K) and mTOR inhibitor that is being tested for cancer chemotherapy but that we now show is also very potent against ATM, ATR and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).

Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma : ATM, ATR and FA in lung carcinoma.[Pubmed:26438152]

BMC Cancer. 2015 Oct 5;15:649.

BACKGROUND: ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas. METHODS: We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes. RESULTS: No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54 T, 201 T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201 T and 239 T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines. CONCLUSIONS: Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibitor ETP-46464 and Chk1 kinase inhibitor UCN-01 were observed and this should be considered in the rationale for Phase I clinical trial design with ATR kinase inhibitors.

Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells.[Pubmed:25560806]

Gynecol Oncol. 2015 Mar;136(3):554-61.

OBJECTIVE: Significant reductions in gynecologic (GYN) cancer mortality and morbidity require treatments that prevent and reverse resistance to chemotherapy and radiation. The objective of this study was to determine if pharmacologic inhibition of key DNA damage response kinases in GYN cancers would enhance cell killing by platinum-based chemotherapy and radiation. METHODS: A panel of human ovarian, endometrial and cervical cancer cell lines were treated with platinum drugs or ionizing radiation (IR) along with small molecule pharmacological kinase inhibitors of Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR). RESULTS: Pharmacologic inhibition of ATR significantly enhanced platinum drug response in all GYN cancer cell lines tested, whereas inhibition of ATM did not enhance the response to platinum drugs. Co-inhibition of ATM and ATR did not enhance platinum kill beyond that observed by inhibition of ATR alone. By contrast, inhibiting either ATR or ATM enhanced the response to IR in all GYN cancer cells, with further enhancement achieved with co-inhibition. CONCLUSIONS: These studies highlight actionable mechanisms operative in GYN cancer cells with potential to maximize response of platinum agents and radiation in newly diagnosed as well as recurrent gynecologic cancers.

Simian virus 40 large T antigen induces IFN-stimulated genes through ATR kinase.[Pubmed:24799566]

J Immunol. 2014 Jun 15;192(12):5933-42.

Polyomaviruses encode a large T Ag (LT), a multifunctional protein essential for the regulation of both viral and host cell gene expression and productive viral infection. Previously, we have shown that stable expression of LT protein results in upregulation of genes involved in the IFN induction and signaling pathway. In this study, we focus on the cellular signaling mechanism that leads to the induction of IFN responses by LT. Our results show that ectopic expression of SV40 LT results in the induction of IFN-stimulated genes (ISGs) in human fibroblasts and confers an antiviral state. We describe a LT-initiated DNA damage response (DDR) that activates IFN regulatory factor 1, causing IFN-beta production and consequent ISG expression in human cells. This IFN-beta and ISG induction is dependent on ataxia-telangiectasia mutated and Rad3-related (ATR) kinase, but independent of ATM. ATR kinase inhibition using a selective kinase inhibitor (ETP-46464) caused a decrease in IFN regulatory factor 1 stabilization and ISG expression. Furthermore, expression of a mutant LT that does not induce DDR also does not induce IFN-beta and ISGs. These results show that, in the absence of viral infection, LT-initiated activation of ATR-dependent DDR is sufficient for the induction of an IFN-beta-mediated innate immune response in human cells. Thus, we have uncovered a novel and critical role for ATR as a mediator of antiviral responses utilizing LT.

Description

ETP-46464 is a potent and selective inhibitor of ATR with IC50 of 25 nM.

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