ATR抑制剂抗肿瘤研究进展
Research Progress of ATR Inhibitors in Anti-Tumor
DOI: 10.12677/PI.2022.112015, PDF,   
作者: 赵志鹏, 陆 涛#, 焦 宇#：中国药科大学理学院，江苏 南京
关键词: ATR激酶；DNA损伤反应；联合用药；癌症；ATR Kinase； DDR； Combinational Medication； Cancer
摘要: DNA损伤反应(DDR)机制负责检测DNA损伤、暂停细胞周期和启动DNA修复。共济失调毛细血管扩张和Rad3相关蛋白(ATR)是DDR核心的关键激酶，负责感应复制应激(RS)并将其发送到S和G2/M检查点以促进修复。目前，靶向ATR药物已成为多个药企的焦点药物管线，并有多个药物已进入临床阶段。本文阐述了ATR与肿瘤之间的关系，总结了支持ATR抑制剂作为单一疗法以及与化疗、放疗和新型靶向药物如PARP抑制剂联合使用的数据，并讨论了当前的临床试验数据以及将ATR抑制剂应用于临床和识别生物标记物的研究进展。
Abstract: The DNA damage response (DDR) machinery is responsible for detecting DNA damage, pausing the cell cycle and initiating DNA repair. Ataxia telangiectasia and Rad3-related protein (ATR) are a key kinase at the heart of the DDR, responsible for sensing replication stress (RS) and signalling it to S and G2/M checkpoints to facilitate repair. At present, targeted ATR drugs have become the focus of drug pipelines for many pharmaceutical companies, and many drugs have entered the clinical stage. This article describes the relationship between ATR and tumors, summarizes the data supporting the use of ATR inhibitors as monotherapy and in combination with chemotherapy, radiotherapy and new targeted drugs such as PARP inhibitors, and discusses current clinical trial data and the use of ATR research progress in the application of inhibitors to the clinic and the identification of biomarkers.
文章引用：赵志鹏, 陆涛, 焦宇. ATR抑制剂抗肿瘤研究进展[J]. 药物资讯, 2022, 11(2): 113-126. https://doi.org/10.12677/PI.2022.112015

参考文献

[1] Qiu, Z., Oleinick, N.L. and Zhang, J. (2018) ATR/CHK1 Inhibitors and Cancer Therapy. Radiotherapy & Oncology, 126, 450-464. [Google Scholar] [CrossRef] [PubMed]
[2] Jackson, S.P. and Bartek, J. (2009) TheDNA-Damage Response in Human Biology and Disease. Nature, 461, 1071-1078. [Google Scholar] [CrossRef] [PubMed]
[3] Marchal, A. and Zou, L. (2013) DNA Damage Sensing by the ATM and ATRkinase. Cold Spring Harbor Perspectives in Biology, 5, Article ID: a012716. [Google Scholar] [CrossRef] [PubMed]
[4] Shiotani, B. and Zou, L. (2009) ATR Signaling at a Glance. Journal of Cell Science, 122, 301-304. [Google Scholar] [CrossRef] [PubMed]
[5] Enriquez-Rios, V., Dumitrache, L.C., Downing, S.M., et al. (2017) DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neu-Rogenesis. Journal of Neuroscience, 37, 893-905. [Google Scholar] [CrossRef] 
[6] Foote, K.M, Lau, A. and Nissink, JW. (2015) Drugging ATR: Progress in the Development of Specific Inhibitors for the Treatment of Cancer. Future Medicinal Chemistry, 7, 873-891. [Google Scholar] [CrossRef] [PubMed]
[7] Weber, A.M. and Ryan, A.J. (2015) ATM and ATR as Thera-peutic Targets in Cancer. Pharmacology & Therapeutics, 149, 124-138. [Google Scholar] [CrossRef] [PubMed]
[8] Murga, M., Bunting, S., Montana, M.F., et al. (2009) A Mouse Model of ATR-Seckel Shows Embryonic Replicative Stress and Accelerated Aging. Nature Genetics, 41, 891-898. [Google Scholar] [CrossRef] [PubMed]
[9] Dillon, M.T., Barker, H.E., Pedersen, M., et al. (2017) Radiosensiti-zation by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei. Molecular Cancer Therapeutics, 16, 25-34. [Google Scholar] [CrossRef] 
[10] Reaper, P.M., Griffiths, M.R., Long, J.M., et al. (2011) Selective Killing of ATM- or p53-Deficient Cancer Cells through Inhibition of ATR. Nature Chemical Biology, 7, 428-430. [Google Scholar] [CrossRef] [PubMed]
[11] Middleton, F.K., Pollard, J.R. and Curtin, N.J. (2018) The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation. Cancers, 10, Article No. 275. [Google Scholar] [CrossRef] [PubMed]
[12] Barsanti, P.A., Pan, Y., Lu, Y., et al. (2015) Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors. ACS Medicinal Chemistry Letter, 6, 42-46. [Google Scholar] [CrossRef] [PubMed]
[13] Kwok, M., Davies, N., Agathanggelou, A., et al. (2016) ATR Inhibition Induces Synthetic Lethality and Overcomes Chemoresistance in TP53 or ATM-Defective Chronic Lym-phocytic Leukemia Cells. Blood, 127, 582-595. [Google Scholar] [CrossRef] [PubMed]
[14] Peasland, A., Wang, L.Z., Rowling, E., et al. (2011) Identifi-cation and Evaluation of a Potent Novel ATR Inhibitor, NU6027, in Breast and Ovarian Cancer Cell Lines. British Jour-nal of Cancer, 105, 372-381. [Google Scholar] [CrossRef] [PubMed]
[15] Fokas, E., Prevo, R., Pollard, J.R., et al. (2012) Targeting ATR in Vivo Using the Novel Inhibitor VE-822 Results in Selective Sensitization of Pancreatic Tumors to Radiation. Cell Death & Diseases, 3, Article No. e441. [Google Scholar] [CrossRef] [PubMed]
[16] Ramachandran, S.A., Jadhavar, P.S., Singh, M.P., et al. (2017) Dis-covery of Pyrazolopyrimidine Derivatives as Novel Inhibitors of Ataxia Telangiectasia and Rad3 Related Protein (ATR). Bioorganic & Medicinal Chemistry Letters, 27, 750-754. [Google Scholar] [CrossRef] [PubMed]
[17] Charrier, J.D., Durrant, S.J., Golec, J.M., et al. (2011) Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mu-tated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents. Journal of Medicinal Chemistry, 54, 2320-2330. [Google Scholar] [CrossRef] [PubMed]
[18] Petermann, E. and Caldecott, K.W. (2006) Evidence That the ATR/Chk1 Pathway Maintains Normal Replication Fork Progression during Unperturbed S Phase. Cell Cycle, 5, 2203-2209.
[19] Knegtel, R., Charrier, J.D., Durrant, S., Davis, C., O’Donnell, M., Storck, P., MacCormick, S., et al. (2019) Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor. Journal of Medicinal Chemistry, 62, 5547-5561. [Google Scholar] [CrossRef] [PubMed]
[20] Karanika, S., Karantanos, T., Li, L., et al. (2015) DNA Dam-age Response and Prostate Cancer: Defects Regulation and Therapeutic Implications. Oncogene, 34, 2815-2822. [Google Scholar] [CrossRef] [PubMed]
[21] Cossar, L., Schache, A., Risk, J., et al. (2017) Modulating the DNA Damage Response to Improve Treatment Response in Cervical Cancer. Clinical Oncology, 29, 626-634. [Google Scholar] [CrossRef] [PubMed]
[22] Foote, K.M., Blades, K., Cronin, A., Fillery S, Guichard, S.S., Hassall, L., Hickson, I., et al. (2013) Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl) cyclo-propyl] pyrimidin-2-yl-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in vivo Antitumor Activity. Journal of Medicinal Chemistry, 56, 2125-2138. [Google Scholar] [CrossRef] [PubMed]
[23] Sangster-Guity, N., Conrad, B.H., Papadopoulos, N., et al. (2011) ATR Mediates Cisplatin Resistance in a p53 Genotype-Specific Manner. Oncogene, 30, 2526-2533. [Google Scholar] [CrossRef] [PubMed]
[24] Chen, T., Middleton, F.K., Falcon, S., et al. (2015) Development of Pharmacodynamic Biomarkers for ATR Inhibitors. Molecular Oncology, 9, 463-472. [Google Scholar] [CrossRef] [PubMed]
[25] Chen, H., Lisby, M. and Symington, L.S. (2013) RPA Coordi-nates DNA End Resection and Prevents Formation of DNA Hairpins. Molecular Cell, 50, 589-600. [Google Scholar] [CrossRef] [PubMed]
[26] Liu, Q., Kirubakaran, S., Hur, W., et al. (2012) Kinome-Wide Selectivity Profiling of ATP-Competitive Mammalian Target of Rapamycin (mTOR) Inhibitors and Characterization of Their Binding Kinetics. Journal of Biological Chemistry, 287, 9742-9752. [Google Scholar] [CrossRef] 
[27] Liu, Q., Xu, C., Kirubakaran, S., et al. (2013) Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR. Cancer Research, 73, 2574-2586. [Google Scholar] [CrossRef] 
[28] Toledo, L.I., Murga, M., Fernandez-Capetillo, O. (2011) Targeting ATR and Chk1 Kinases for Cancer Treatment: A New Model for New (and Old) Drugs. Molecular Oncology, 5, 368-373. [Google Scholar] [CrossRef] [PubMed]
[29] Foote, K.M., Nissink, J.W.M., Mcguire, T., et al. (2018) Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Re-lated (ATR) Kinase with Application as an Anticancer Agent. Journal of Medicinal Chemistry, 61, 9889-9907. [Google Scholar] [CrossRef] [PubMed]
[30] Do, K. and Chen, A.P. (2013) Molecular Pathways: Targeting PARP in Cancer Treatment. Clinical Cancer Research, 19, 977-984.
[31] Gaudio, E., Tarantelli, C., Spriano, F., et al. (2019) Abstract 274: The ATR inhibitor BAY 1895344 Shows Strong Preclinical Activity in Lymphomas and Appears Associated with Specific Gene Expression Signatures. Cancer Research, 79, 2740. [Google Scholar] [CrossRef] 
[32] Cepeda, V., Fuertes, M.A., Castilla, J., et al. (2006) Poly(ADP-Ribose)Polymerase-1(PARP-1) Inhibitors in Cancer Chemotherapy. Recent Patents on Anti-Cancer Drug Discovery, 1, 39-53.
[33] Sarkaria, J.N., Busby, E.C., Tibbetts, R.S., et al. (1999) Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine. Cancer Research, 59, 4375-4382.
[34] Nishida, H., Tatewaki, N., Nakajima, Y., et al. (2009) Inhibition of ATR Protein Kinase Activity by Schisandrin B in DNA Damage Response. Nu-cleic Acids Research, 37, 5678-5689. [Google Scholar] [CrossRef] [PubMed]
[35] Peasland, A., Wang, L.Z., Rowling, E., et al. (2011) Identification and Evaluation of a Potent Novel ATR Inhibitor, NU6027, in Breast and Ovarian Cancer Cell Lines. British Journal of Cancer, 105, 372-381.
[36] Barsanti, P.A., Aversa, R.J., Jin, X., et al. (2015) Struc-ture-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo [1,5-a]pyrazines as ATR Inhibitors. ACS Medicinal Chemistry Letters, 6, 37-41. [Google Scholar] [CrossRef] [PubMed]
[37] Combes, E., Andrade, A.F., Tosi, D., et al. (2019) Inhibition of Atax-ia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immun-ity in Colorectal Cancer. Cancer Research, 79, 2933-2946. [Google Scholar] [CrossRef] 
[38] Bradbury, A., Hall, S., Curtin, N., et al. (2020) Targeting ATR as Cancer Therapy: A New Era for Synthetic Lethality and Synergistic Combinations? Pharmacology & Therapeu-tics, 207, Article ID: 107450. [Google Scholar] [CrossRef] [PubMed]
[39] Wallez, Y., Dunlop, C.R., Johnson, T.I., et al. (2018) The ATR Inhibitor AZD6738 Synergizes with Gemcitabine in Vitro and in Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression. Molecular Cancer Therapeutics, 17, 1670-1682. [Google Scholar] [CrossRef] 
[40] Lecona, E. and Fernandez-Capetillo, O. (2018) Targeting ATR in Cancer. Nature Reviews Cancer, 18, 586-595. [Google Scholar] [CrossRef] [PubMed]
[41] Vendetti, F.P., Leibowitz, B.J., Barnes, J., et al. (2017) Pharma-cologic ATM But Not ATR Kinase Inhibition Abrogates p21-Dependent G1 Arrest and Promotes Gastrointestinal Syn-drome after Total Body Irradiation. Scientific Reports, 7, Article No. 41892. [Google Scholar] [CrossRef] [PubMed]
[42] Sarkaria, J.N., Tibbetts, R.S., Busby, E.C, et al. (1998) Inhibition of Phosphoinositide 3-Kinase Related Kinases by the Radio Sensitizing Agent Wortmannin. Cancer Research, 58, 4375-4382.
[43] Grara, X., Luca, A.D., Sang, N., et al. (1994) PITALRE, a Nuclear CDC2-Related Protein Kinase That Phosphorylates the Retinoblastoma Protein in Vitro. Proceedings of the National Academy of Sciences of the United States of America, 91, 3834-3838. [Google Scholar] [CrossRef] [PubMed]
[44] Couch, F.B., Bansbach, C.E., Driscoll, R., et al. (2013) ATR Phosphorylates SMARCAL1 to Prevent Replication Fork Collapse. Genes & Develop-ment, 27, 1610-1623. [Google Scholar] [CrossRef] [PubMed]
[45] Pleschke, J.M., Kleczkowska, H.E., Strohm, M., et al. (2000) Poly(ADP-Ribose)Binds to Specific Domains in DNA Damage Checkpoint Proteins. Journal of Bio-logical Chemistry, 275, 40974-40980.
[46] Deng, S.K., Yin, Y, Petes, T.D., et al. (2015) Mre11-Sae2 and RPA Col-laborate to Prevent Palindromic Gene Amplification. Molecular Cell, 60, 500-508. [Google Scholar] [CrossRef] [PubMed]