Azd6738

Manufactured by Selleck Chemicals

Sourced in United States

AZD6738 is a chemical compound used as a research tool in laboratory settings. It functions as an inhibitor of ATR kinase, a protein involved in the cellular response to DNA damage. AZD6738 is commonly utilized in scientific investigations to study various biological processes and pathways related to DNA repair mechanisms.

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ATRi AZD6738 (2 citations)

50 protocols using azd6738

Drug Solubilization and Preparation

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Olaparib was purchased from Cambridge Biosciences (Cambridgeshire, UK). VE-821 and AZD6738 were purchased from Selleckchem, UK. Each was dissolved in 100% DMSO to give a 10 mM stock. Temozolomide and topotecan were purchased from Sigma-Aldrich (Gillingham, Dorset, UK) and dissolved in 100% DMSO to give a 100 mM stock.

King D., Southgate H.E., Roetschke S., Gravells P., Fields L., Watson J.B., Chen L., Chapman D., Harrison D., Yeomanson D., Curtin N.J., Tweddle D.A, & Bryant H.E. (2021). Increased Replication Stress Determines ATR Inhibitor Sensitivity in Neuroblastoma Cells. Cancers, 13(24), 6215.

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Evaluating Small Molecule Inhibitors

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KU-55933, AZD6738, and LY2606368 were purchased from Selleck Chemicals. Olaparib was purchased from BioVision Inc. Hydroxyurea, cisplatin, mitomycin C (MMC), camptothecin, and etoposide were purchased from Sigma-Aldrich.

Su D., Feng X., Colic M., Wang Y., Zhang C., Wang C., Tang M., Hart T, & Chen J. (2020). CRISPR/CAS9-based DNA damage response screens reveal gene-drug interactions. DNA repair, 87, 102803.

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Inhibitor Procurement and Preparation

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AZD7762 (CHK1 inhibitor), AZD6738 (ATR inhibitor), EPZ6438 (EZH2 inhibitor, also called Tazemetostat), KU-60019 (ATM inhibitor) were purchased from Selleckchem (Houston, TX, USA). GSK126 (an inhibitor of EZH2 methyltransferase activity) was purchased from Cayman Chemical (Ann Arbor, Michigan, USA). All drugs were dissolved in dimethyl sulfoxide (DMSO, Sigma-Aldrich, St. Louis, MO, USA) and stored at -20 °C.

Wen Y., Hou Y., Yi X., Sun S., Guo J., He X., Li T., Cai J, & Wang Z. (2021). EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells. Theranostics, 11(4), 1795-1813.

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Immortalized CEnC Lines: Telomerase and SV40

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Telomerase (normal - HCEnC-21T) and SV40 T antigen (Normal 67F and FECD 67F, 54F, 74F) immortalized CEnC lines used in this study were previously generated in our laboratory (Schmedt et al., 2012 (link)). All cells were cultured in Chen’s medium (Konomi et al., 2005 (link)) (OptiMEM-I; Invitrogen, Carlsbad, CA), containing 8% fetal bovine serum (HyClone, Rockford, IL), 5 ng/mL epidermal growth factor (Millipore, Billerica, MA), 100 mg/mL bovine pituitary extract (Invitrogen), 200 mg/L calcium chloride (Sigma-Aldrich, St. Louis, MO), 0.08% chondroitin sulfate (Sigma-Aldrich), 50 mg/mL gentamicin (Invitrogen), and 1:100 diluted antibiotic/antimycotic solution (Sigma-Aldrich) at 37 degrees and 5% CO₂. For UVA irradiation, two 19.5-inch UVA tubes (XX-15L; Analytik Jena US LLC) emitting 365 nm light (irradiance: 14.77 mW/cm²) were used to irradiate normal CEnCs (HCEnC-21T) at a fluence of 25J/cm², followed by a recovery period of 24 hours (unless otherwise stated) in Opti-MEM. ATR inhibition was achieved by pre-treatment for 2-hours, (as well as 24-hour recovery following UVA) with 5μm AZD6738 (Selleckchem, Houston, TX). Cells were arrested in G2/M using 10µM RO3306 (RO) (Sigma-Aldrich) in opti-MEM for 24-hours. For DQ, 24-hours post-UVA irradiation, cells were treated with a combination of 30µM quercetin (Sigma-Aldrich) and 200nm dasatinib (Sigma-Aldrich) for 5-hours.

White T.L., Deshpande N., Kumar V., Gauthier A.G, & Jurkunas U.V. (2021). Cell cycle re-entry and arrest in G2/M phase induces senescence and fibrosis in Fuchs Endothelial Corneal Dystrophy. Free radical biology & medicine, 164, 34-43.

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Antibody Validation for Cell Signaling

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Antibodies for Chk1 (25887–1-AP), H2AX (10856–1-AP), P53 (10442–1-AP), ATR (19787–1-AP), and CTPS1 (15914–1-AP) were purchased from ProteinTech. Antibodies for MYC (ab32072), CTPS2 (ab196016), and β-actin (ab6276) were purchased from Abcam. Antibodies for phospho-Chk1 (Ser345; #2348), phospho-histone H2AX (Ser139; #9718), phospho-ATR (Thr1989; #58014), and cleaved caspase-3 (Asp175; #9661) were purchased from Cell Signaling Technology. Antibody for HA (Sc-7392) was purchased from Santa Cruz. Doxycycline (S5159), VX-680 (S1048), Purvalanol A (S7793), cytidine (S2053), uridine (S2029), guanosine (S2439), adenosine (S1647), VE-822 (S7102), hydroxyurea (S1896), and AZD6738 (S7693) were purchased from Selleck Chemicals. BMH-21 (B4896) was from APExBIO. BAY-1895344 (HY-101566A), CX-3543 (HY-14776), and CX-5461 (HY-13323) were from MedchemExpress. 3-Deazauridine (sc-394445) was purchased from Santa Cruz.

Sun Z., Zhang Z., Wang Q.Q, & Liu J.L. (2022). Combined Inactivation of CTPS1 and ATR Is Synthetically Lethal to MYC-Overexpressing Cancer Cells. Cancer Research, 82(6), 1013-1024.

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Inhibitor Preparation and Cell Culture Protocols

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PARPi (O, olaparib, AZD2281), ATRi (A, ceralasertib, AZD6738), and CHK1i (C, MK-8776) were purchased from Selleck Chemicals (Houston, TX, USA). The stock solutions of studied inhibitors were separately prepared from powders dissolved in 100% dimethyl sulfoxide (DMSO), aliquoted, and stored at −80 °C for up to a maximum of six months. RPMI 1640 and DMEM culture media, heat-inactivated fetal bovine serum (HI-FBS), and trypsin-EDTA were obtained from Gibco (Thermo Fisher Scientific, Waltham, MA, USA). Details concerning other key reagents used in the studies are included in Section 2 and Supplementary Tables (Tables S1–S3). Chemicals and solvents were obtained from Sigma-Aldrich (Saint Louis, MO, USA) or Avantor Performance Materials Poland S.A. (Gliwice, Poland).

Biegała Ł., Gajek A., Marczak A, & Rogalska A. (2023). Olaparib-Resistant BRCA2MUT Ovarian Cancer Cells with Restored BRCA2 Abrogate Olaparib-Induced DNA Damage and G2/M Arrest Controlled by the ATR/CHK1 Pathway for Survival. Cells, 12(7), 1038.

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Comprehensive Toolkit for Cancer Research

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RSL3 (S8155), neratinib (S2150), lapatinib (S2111), gefitinib (S1025), ML210 (S0788), afatinib (S1011), dacomitinib (S2727), sapitinib (S2192), Z-VAD-FMK (S7023), necrostatin-1 (S8037), 3-Methyladenine (3-MA, S2767), tucatinib (S8362), liproxstatin-1 (S7699), erastin (S7242), deferoxamine mesylate (DFO, S5742), deferiprone (S4067), ferrostatin-1 (S7243), cobimetinib (S8041), Trastuzumab (A2007) and AZD6738 (S7693) were obtained from Selleck Chemicals. L-glutathione (G6013) and N-Acetyl-l-cysteine (A9165) were purchased from Sigma-Aldrich. T-DM1 (HY-P9921) was obtained from MedChemExpress.

Park S.Y., Jeong K.J., Poire A., Zhang D., Tsang Y.H., Blucher A.S, & Mills G.B. (2023). Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer. Cell Death & Disease, 14(8), 532.

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Dexamethasone and DMSO Modulate Autophagy

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Dexamethasone and dimethyl sulfoxide (DMSO) were purchased from Sigma (St. Louis, MO, USA). Chloroquine (CQ, an autophagy inhibitor) and AZD6738 (an ATR inhibitor) were purchased from Selleck Chemicals (Houston, TX, USA). Annexin V Apoptosis Detection Kit APC/PI was obtained from BD Biosciences (NJ, USA). The following primary antibodies were used: anti-HMGB1 (Cell Signaling Technology (CST), #6893), anti-caspase-3 (CST, #6893), anti-Bcl-2 (CST, #6893), anti-Bcl-xl (CST, #6893), anti-PARP (CST, #6893), anti-DEPTOR (CST, #6893), anti-mTOR (CST, #6893), anti-p-mTOR (ser2448) (CST, #6893), anti-p70S6K (CST, #6893), anti-p-p70S6K (Thr389) (CST, #6893), anti-Akt (CST, #6893), anti-p-AKT (ser473) (CST, #6893), anti-LC3A/B (CST, #6893), anti-γH2A.X (CST, #9718), anti-Rad51 (Abcam, ab133534), Anti-β-actin (Sigma-Aldrich, A1978) and anti-GAPDH (ProteinTech, No. 60004–1).

Guo X., He D., Zhang E., Chen J., Chen Q., Li Y., Yang L., Yang Y., Zhao Y., Wang G., He J, & Cai Z. (2018). HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair. Journal of Experimental & Clinical Cancer Research : CR, 37, 205.

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Preparation and Dissolution of Chemotherapeutics

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Doxorubicin (Sigma-Aldrich), epirubicin, AZD6738 and KU60019 (Selleck Chemicals) were dissolved in DMSO (Sigma). 5-fluorodeoxyuridine (FUdR; Sigma) and cisplatin (Abcam) were dissolved in sterile cell culture water (Sigma). Carboplatin (Hospiara, UK) was supplied at 10 mg/mL. CV6-530, a small molecule tool compound shown to inhibit dUTPase, was supplied by CV6 Therapeutics in DMSO. All drugs were sterile filtered and aliquoted to avoid freeze-thaw cycles. For in vivo studies, compounds were purchased from Sigma-Aldrich.

Davison C., Morelli R., Knowlson C., McKechnie M., Carson R., Stachtea X., McLaughlin K.A., Prise V.E., Savage K., Wilson R.H., Mulligan K.A., Wilson P.M., Ladner R.D, & LaBonte M.J. (2021). Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer. NPJ Breast Cancer, 7, 38.

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Functionally-Instructed Compound Library

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As ATRi, we used AZD6738 (Celasertib, Selleckchem, Houston, TX, US) at a stock concentration of 50 mM in dimethylsulfoxide (DMSO) and Berzosertib (ChemiTek, Indianapolis, IN, US) also diluted at 50 mM in DMSO as ATR inhibitors. Furthermore, we generated a compound library based on the functionally-instructed targets for drug screens. All compounds are outlined in Supplementary Table ST3.

Walter B., Hirsch S., Kuhlburger L., Stahl A., Schnabel L., Wisser S., Haeusser L.A., Tsiami F., Plöger S., Aghaallaei N., Dick A.M., Skokowa J., Schmees C., Templin M., Schenke-Layland K., Tatagiba M., Nahnsen S., Merk D.J, & Tabatabai G. (2024). Functionally-instructed modifiers of response to ATR inhibition in experimental glioma. Journal of Experimental & Clinical Cancer Research : CR, 43, 77.

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