Skip to main content
SpringerLink
Log in

Targeting ATM for Cancer Therapy: Prospects for Drugging ATM

  • Chapter
  • First Online:
Targeting the DNA Damage Response for Anti-Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

As discussed in the previous chapter, the rationale for inhibition of ATM as a therapeutic strategy in cancer is both scientifically sound and well explored. The use of experimental models and, thereafter, the availability of tool compounds to inhibit the target, has allowed the role of ATM in cell signalling to be refined and has highlighted the potential utility of ATM inhibition for therapeutic intervention. The role of ATM as the central DNA damage response (DDR) protein, the high sensitivity of cells from A-T patients, who lack functional ATM, to IR and DNA damaging chemotherapy, and the consequences of knocking down ATM in otherwise proficient cells, have been well described and support ATM as a pharmaceutical target of interest. The somewhat atypical nature of ATM (a member of the PIKK family of kinases), combined with the size of the protein, have brought some unique challenges and opportunities to the discovery of inhibitors of ATM. The development of robust, high-throughput biochemical assays for ATM inhibition has proved challenging, thereby requiring the establishment of less conventional assays to facilitate drug discovery efforts. However, the availability of early compounds that were shown to share features of ATM loss (i.e. bringing about sensitisation of cells to IR induced cell damage and death), helped advance the process and over the past decade the research into ATM inhibition has advanced as the quality of available inhibitors has improved. In this chapter, we will explore the evolution of ATM inhibitors from crude but effective tools, through highly selective tool compounds and ultimately to the development of compounds with potential clinical utility as therapeutics for cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aguilar-Quesada R, Muñoz-Gámez JA, Martín-Oliva D, Peralta A, Valenzuela MT, Matínez-Romero R, Quiles-Pérez R, Menissier-de Murcia J, de Murcia G, Ruiz de Almodóvar M, Oliver FJ (2007) Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition. BMC Mol Biol 8:29–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ajaz M, Jefferies S, Brazil L, Watts C, Chalmers A (2014) Current and investigational drug strategies for glioblastoma. Clin Oncol 26:419–430

    Article  CAS  Google Scholar 

  • Andrs M, Korabecny J, Jun D, Hodny Z, Bartek J, Kuca K (2015) Phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring. J Med Chem 58:41–71

    Article  CAS  PubMed  Google Scholar 

  • Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    Article  CAS  PubMed  Google Scholar 

  • Banin S, Moyal I, Shieh SY, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y (1998) Enhanced phosporylation of p53 by ATM in response to DNA damage. Science 281:1674–1677

    Article  CAS  PubMed  Google Scholar 

  • Barazzuol L, Rickett N, Ju L, Jeggo PA (2015) Low levels of endogenous or X-ray-induced DNA double-strand breaks activate apoptosis in adult neural stem cells. Cell Sci 128:3597–3606

    Article  CAS  Google Scholar 

  • Batey MA, Zhao Y, Kyle S, Richardson C, Slade A, Martin NMB, Lau A, Newell DR, Curtin NJ (2013) Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer. Mol Cancer Ther 12:959–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beamish H, Lavin MF (1994) Radiosensitivity in ataxia-telangiectasia: anomalies in radiation-induced cell cycle delay. Int J Radiat Biol 65:175–184

    Article  CAS  PubMed  Google Scholar 

  • Bennetzen MV, Larsen DH, Bunkenborg J, Bartek J, Lukas J, Anderson JS (2010) Site-specific phosphorylationdynamics of the nuclear proteome during the DNA damage response. Mol Cell Proteomics 9:1314–1323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biddlestone-Thorpe L, Sajjad M, Rosenberg E, Beckta JM, Valerie NCK, Tokarz M, Adams BR, Wagner AF, Khalil A, Gilfor D, Golding SE, Deb S, Temesi DG, Lau A, O’Connor MJ, Choe KS, Parada LF, Lim SK, Mukhopadhyay ND, Valerie K (2013) ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clin Cancer Res 19:3189–3200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blasina A, Price BD, Turenne GA, McGowan CH (1999) Caffeine inhibits the checkpoint kinase ATM. Curr Biol 9:1135–1138

    Article  CAS  PubMed  Google Scholar 

  • Bracey TS, Williams AC, Paraskeva C (1997) Inhibition of radiation-induced G2 delay potentiates cell death by apoptosis and/or the induction of giant cells in colorectal tumor cells with disrupted p53 function. Clin Cancer Res 3:1371–1381

    PubMed  CAS  Google Scholar 

  • Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917

    Article  CAS  PubMed  Google Scholar 

  • Choi S, Gamper AM, White JS, Bakkenist CJ (2010) Inhibition of ATM kinase activity does not phenocopy ATM protein disruption: implications for the clinical utility of ATM kinase inhibitors. Cell Cycle 9:4052–4057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi S, Toledo LI, Fernandez-Capetillo O, Bakkenist CJ (2011) CGK733 does not inhibit ATM or ATR kinase activity in H460 human lung cancer cells. DNA Repair 10:1000–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daniel JA, Pellegrini M, Lee B-S, Guo Z, Filsuf D, Belkina NV, You Z, Paull TT, Sleckman BP, Feigenbaum L, Nussenzweig A (2012) Loss of ATM kinase activity leads to embryonic lethality in mice. J Cell Biol 198:295–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Degorce SL, Barlaam B, Cadogan E, Dishington A, Ducray R, Glossop SC, Hassall LA, Lach F, Lau A, McGuire TM, Nowak T, Ouvry G, Pike KG, Thomason AG (2016) Discovery of novel 3-quinline carboxamides as potent, selective and orally bioavailable inhibitors of ataxia telangiectasia mutated (ATM) kinase. J Med Chem 59:6281–6292

    Article  CAS  PubMed  Google Scholar 

  • Delgado-López PD, Corrales-García EM (2016) Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol 18:1062–1071

    Article  CAS  PubMed  Google Scholar 

  • Ding X, Rose JP, Van Gelder J (2012) Developability assessment of clinical drug products with maximum absorbable doses. Int J Pharm 427:260–269

    Article  CAS  PubMed  Google Scholar 

  • Durant ST, Karlin J, Pike K, Colclough N, Mukhopadhyay N, Ahmad SF, Bekta JM, Tokarz M, Bardelle C, Hughes G, Patel B, Thomason A, Cadogan E, Barrett I, Lau A, Pass M, Valerie K (2016) Blood-brain barrier penetrating ATM inhibitor (AZ32) radiosensitises intracranial gliomas in mice. Cancer Res 76(suppl):3041

    Article  Google Scholar 

  • Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NMB, Jackson SP, Smith GCM, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  CAS  PubMed  Google Scholar 

  • Fedier A, Schlamminger M, Schwarz VA, Haller U, Howell SB, Fink D (2003) Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites. Ann Oncol 14:938–945

    Article  CAS  PubMed  Google Scholar 

  • Foray N, Priestley A, Alsbeih G, Badie C, Capulas EP, Arlett CF, Malaise EP (1997) Hypersensitivity of ataxia telangiectasia fibroblasts to ionizing radiation is associated with a repair deficiency of DNA double-strand breaks. Int J Radiat Biol 72:271–283

    Article  CAS  PubMed  Google Scholar 

  • Fruman DA, Meyers RE, Cantley LC (1998) Phosphoinositide kinases. Annu Rev Biochem 67:481–507

    Article  CAS  PubMed  Google Scholar 

  • Furet P, Caravatti G, Guagnano V, Lang M, Meyer T, Schoepfer J (2008) Entry into a new class of protein kinase inhibitors by pseudo ring design. Bioorg Med Chem Lett 18:897–900

    Article  CAS  PubMed  Google Scholar 

  • Gatz SA, Ju L, Gruber R, Hoffmann E, Carr AM, Wang ZQ, Liu C, Jeggo PA (2011) Requirement for DNA ligase IV during embryonic neuronal development. J Neurosci 31:10088–10100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA, O’Connor MJ, Povirk LF, van Meter T, Valerie K (2009) Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther 8:2894–2902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Golding SE, Rosenberg E, Adams BR, Wignarajah S, Beckta JM, O’Connor MJ, Valerie K (2012) Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle 11:1167–1173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gosink EC, Chong MJ, McKinnon PJ (1999) Ataxia telangiectasia mutated deficiency affects astrocyte growth but not radiosensitivity. Cancer Res 59:5294–5298

    PubMed  CAS  Google Scholar 

  • Guo K, Shelat A, Guy RK, Kastan MB (2014) Development of a cell-based, high-throughput screening assay for ATM kinase inhibitors. J Biomol Screen 19:538–546

    Article  CAS  PubMed  Google Scholar 

  • Herzog KH, Chong MJ, Kapsetaki M, Morgan JI, McKinnon PJ (1998) Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 280:1089–1091

    Article  CAS  PubMed  Google Scholar 

  • Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NMB, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GC (2004) Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 64:9152–9159

    Article  CAS  PubMed  Google Scholar 

  • Hilgers AR, Smith DP, Biermacher JJ, Day JS, Jensen JL, Sims SM, Adams WJ, Friis JM, Palandra J, Hosley JD, Shobe EM, Burton PS (2003) Predicting oral absorption of drugs: a case study with a novel class of antimicrobial agents. Pharm Res 20:1149–1155

    Article  CAS  PubMed  Google Scholar 

  • Hollick JJ, Rigoreau LJM, Cano-Soumillac C, Cockcroft X, Curtin NJ, Frigerio M, Golding BT, Guiard S, Hardcastle IR, Hickson I, Hummersone MG, Menear KA, Martin NMB, Matthews I, Newell DR, Ord R, Richardson CJ, GCM S, Griffin RJ (2007) Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase. J Med Chem 50:1958–1972

    Article  CAS  PubMed  Google Scholar 

  • Houldsworth J, Lavin M (1980) Effect of ionizing radiation on DNA synthesis in ataxia teleangiectasia cells. Nucleic Acids Res 8:3709–3720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Izzard RA, Jackson SP, Smith GCM (1999) Competitive and non-competitive inhibition of the DNA dependent protein kinase. Cancer Res 59:2581–2586

    PubMed  CAS  Google Scholar 

  • Johnson KC, Swindell AC (1996) Guidance in the setting of drug particle size specification to minimize variability in absorption. Pharm Res 3:1795–1798

    Article  Google Scholar 

  • Kaelin WGJ (2005) The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5:689–698

    Article  CAS  PubMed  Google Scholar 

  • Kahn J, Allen J, Karlin JD, Ahmad S, Sule A, Tokarz M, Henderson A, Mukhopadhyay ND, Pike K, Colclough N, Pass M, Durant S, Valerie K (2017) Next-generation ATM kinase inhibitors under development radiosensitize glioblastoma with conformal radiation in a mouse orthotopic model. Int J Rad Oncol 99:E600–E601

    Article  Google Scholar 

  • Karve S, Werner ME, Sukumar R, Cummings ND, Copp JA, Wang EC, Li C, Sethi M, Chen RC, Pacold ME, Wang AZ (2012) Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery. Proc Natl Acad Sci U S A 109:8230–8235

    Article  PubMed  PubMed Central  Google Scholar 

  • Kastan MB, Zhan Q, El-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJJ (1992) A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71:587–597

    Article  CAS  PubMed  Google Scholar 

  • Kim SY, Rhee JG, Song X, Prochownik EV, Spitz DR, Lee YJ (2012) Breast cancer stem cell-like cells are more sensitive to ionizing radiation than non-stem cells: role of ATM. PLoS One 7:e50423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knight ZA, Shokat KM (2005) Features of selective kinase inhibitors. Chem Biol 12:621–637

    Article  CAS  PubMed  Google Scholar 

  • Knight ZA, Chiang GG, Alaimo PJ, Kenski DM, Ho CB, Coan K, Abraham RT, Shokat KM (2004) Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. Bioorg Med Chem 12:4749–4759

    Article  CAS  PubMed  Google Scholar 

  • Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125:733–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Köcher S, Rieckmann T, Rohaly G, Mansour WY, Dikomey E, Dornreiter I, Dahm-Daphi J (2012) Radiation-induced double-strand breaks require ATM but not Artemis for homologous recombination during S-phase. Nucleic Acids Res 40:8336–8347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Köcher S, Spies-Naumann A, Kriegs M, Dahm-Daphi J, Dornreiter I (2013) ATM is required for the repair of Topotecan-induced replication-associated double-strand breaks. Radiother Oncol 108:409–414

    Article  CAS  PubMed  Google Scholar 

  • Konstantinidou G, Bey EA, Rabellino A, Schuster K, Maira MS, Gazdar AF, Amici A, Boothman DA, Scaglioni PP (2009) Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. Cancer Res 69:7644–7652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kubota E, Williamson CT, Ye R, Elegbede A, Peterson L, Lees-Miller SP, Bebb DG (2014) Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines. Cell Cycle 13:2129–2137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kühne M, Riballo E, Rief N, Ku M, Rothkamm K, Jeggo PA, Löbrich M (2004) A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. Cancer Res 64:500–508

    Article  PubMed  Google Scholar 

  • Lau A, Swinbank KM, Ahmed PS, Taylor DL, Jackson SP, Smith GC, O’Connor MJ (2005) Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase. Nat Cell Biol 7:493–500

    Article  CAS  PubMed  Google Scholar 

  • Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9:759–769

    Article  CAS  PubMed  Google Scholar 

  • Lavin MF, Shiloh Y (1997) The genetic defect in ataxia-telangiectasia. Annu Rev Immunol 15:177–202

    Article  CAS  PubMed  Google Scholar 

  • Lee J-H, Paull TT (2005) ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 Complex. Science 308:551–554

    Article  CAS  PubMed  Google Scholar 

  • Lin X, DeAngelis LM (2015) Treatment of brain metastases. J Clin Oncol 33:3475–3484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu XH, Mattis VB, Wang N, Al-Ramahi I, van den Berg N, Fratantoni SA, Waldvogel H, Greiner E, Osmand A, Elzein K, Xiao J, Dijkstra S, de Pril R, Vinters HV, Faull R, Signer E, Kwak S, Marugan JJ, Botas J, Fischer DF, Svendsen CN, Munoz-Sanjuan I, Yang XW (2014) Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington’s disease. Sci Transl Med 6:268ra178

    Article  CAS  PubMed  Google Scholar 

  • Maira S-M, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, García-Echeverría C (2008) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 7:1851–1863

    Article  CAS  PubMed  Google Scholar 

  • Marine JC, Lozano G (2010) Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ 17:93–102

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka S, Huang M, Elledge SJ (1998) Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282:1893–1897

    Article  CAS  PubMed  Google Scholar 

  • Morgado-Palacin I, Day A, Murga M, Lafarga V, Anton ME, Tubbs A, Chen HT, Ergan A, Anderson R, Bhandoola A, Pike KG, Barlaam B, Cadogan E, Wang X, Pierce AJ, Hubbard C, Armstrong SA, Nussenzweig A, Fernandez-Capetillo O (2016) Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML. Sci Signal 9:ra91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y (2012) Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 72:5588–5599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nadkarni A, Shrivastav M, Mladek AC, Schwingler PM, Grogan PT, Chen J, Sarkaria JN (2012) ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells. J Neuro-Oncol 110:349–357

    Article  CAS  Google Scholar 

  • Page KM (2016) Validation of early human dose prediction: a key metric for compound progression in drug discovery. Mol Pharm 13:609–620

    Article  CAS  PubMed  Google Scholar 

  • Painter RB, Young BR (1980) Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc Natl Acad Sci U S A 77:7315–7317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pike K, Barlaam B, Cadogan E, Campbell A, Colclough N, Davies N, de Almeida C, Degorce S, Didelot M, Dishington A, Ducray R, Durant S, Hassall L, Holmes J, Hughes G, MacFaul P, Mulholland K, McGuire T, Ouvry G, Pass M, RobB G, Stratton N, Wang Z, Wilson J, Zhai B, Zhao K (2018) The Identification of Potent, Selective and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one). J Med Chem, submitted

    Google Scholar 

  • Powell SN, DeFrank JS, Connell P, Eogan M, Preffer F, Dombkowski D, Tang W, Friend S (1995) Differential sensitivity of p53(−) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res 55:1643–1648

    PubMed  CAS  Google Scholar 

  • Powis G, Bonjouklian R, Berggren MM, Gallegos A, Abraham R, Ashendel C, Zalkow L, Matter WF, Dodge J, Grindey G, Vlahos CJ (1994) Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 54:2419–2423

    PubMed  CAS  Google Scholar 

  • Price BD, Youmell MB (1996) The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks induction of p53 following DNA damage. Cancer Res 56:246–250

    PubMed  CAS  Google Scholar 

  • Rainey MD, Charlton ME, Stanton RV, Kastan MB (2008) Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res 68:7466–7474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reaper PM, Griffiths MR, Long JM, Charrier J-D, Maccormick S, Charlton PA, Golec JMC, Pollard JR (2011) Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7:428–430

    Article  CAS  PubMed  Google Scholar 

  • Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PKS, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG (2003) Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58:32–45

    Article  CAS  PubMed  Google Scholar 

  • Rotman G, Shiloh Y (1998) ATM: from gene to function. Hum Mol Genet 7:1555–1563

    Article  CAS  PubMed  Google Scholar 

  • Roy K, Wang L, Makrigiorgos GM, Price BD (2006) Methylation of the ATM promoter in glioma cells alters ionizing radiation sensitivity. Biochem Biophys Res Commun 344:821–826

    Article  CAS  PubMed  Google Scholar 

  • Sarkaria JN, Eshleman JS (2001) ATM as a target for novel radiosensitizers. Semin Radiat Oncol 11:316–327

    Article  CAS  PubMed  Google Scholar 

  • Sarkaria JN, Tibbetts RS, Busby EC, Kennedy AP, Hill DE, Abraham RT (1998) Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 58:4375–4382

    PubMed  CAS  Google Scholar 

  • Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, Abraham RT (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 59:4375–4382

    PubMed  CAS  Google Scholar 

  • Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3:155–168

    Article  CAS  PubMed  Google Scholar 

  • Smith DA, Beaumont K, Maurer TS, Di L (2015) Volume of distribution in drug design. J Med Chem 58:5691–5698

    Article  CAS  PubMed  Google Scholar 

  • Sullivan KD, Gallant-Behm CL, Henry RE, Fraikin JL, Espinosa JM (2012) The p53 circuit board. Biochim Biophys Acta 1825:229–244

    PubMed  PubMed Central  CAS  Google Scholar 

  • Sultana R, McNeill DR, Abbotts R, Mohammed MZ, Zdzienicka MZ, Qutob H, Seedhouse C, Laughton CA, Fischer PM, Patel PM, Wilson DM, Madhusudan S (2012) Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors. Int J Cancer 131:2433–2444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sultana R, Abdel-Fatah T, Abbotts R, Hawkes C, Albarakati N, Seedhouse C, Ball G, Chan S, E a R, Ellis IO, Madhusudan S (2013) Targeting XRCC1 deficiency in breast cancer for personalized therapy. Cancer Res 73:1621–1634

    Article  CAS  PubMed  Google Scholar 

  • Taylor AMR, Harnden DG, Arlett CF, Harcourt SA, Lehmann AR, Stevens S, Bridges BA (1975) Ataxia teleangiectasia: a human mutation with abnormal radiation sensitivity. Nature 258:427–429

    Article  CAS  PubMed  Google Scholar 

  • Teng P, Bateman NW, Darcy KM, Hamilton CA, Larry G, Bakkenist CJ, Conrads TP (2015) Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinumor radiation response in ovarian, endometrial, and cervical cancer cells. Gynecol Oncol 136:554–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, Oyarzabal J, Pastor J, Bischoff JR, Fernandez-Capetillo O (2011) A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 18(6):721–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ui M, Okada T, Hazeki K, Hazeki O (1995) Wortmannin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase. Trends Biochem Sci 20:303–307

    Article  CAS  PubMed  Google Scholar 

  • Vendetti FP, Leibowitz BJ, Barnes J, Schamus S, Kiesel BF, Abberbock S, Conrads T, Clump DA, Cadogan E, O’Connor MJ, Yu J, Beumer JH, Bakkenist CJ (2017) Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Sci Rep 7:41892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one. J Biol Chem 269:5241–5248

    PubMed  CAS  Google Scholar 

  • Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL (2000) Structural determinants of phosphoinositide3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6:909–919

    Article  CAS  PubMed  Google Scholar 

  • Waring MJ, Johnstone C, McKerrecher D, Pike KG, Robb G (2011) Matrix-based multiparameter optimisation of glucokinase activators: the discovery of AZD1092. Med Chem Commun 2:775–779

    Article  CAS  Google Scholar 

  • Weber AM, Ryan AJ (2015) ATM and ATR as therapeutic targets in cancer. Pharmacol Ther 149:124–138

    Article  CAS  PubMed  Google Scholar 

  • Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJS, Smith G, Powell JE, Rudzki Z, Kearns P, Moss PAH, Taylor AMR, Stankovic T (2010) The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood 116:4578–4587

    Article  CAS  PubMed  Google Scholar 

  • White JS, Choi S, Bakkenist CJ (2010) Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange. Sci Signal 3:ra44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Won J, Kim M, Kim N, Ahn JH, Lee WG, Kim SS, Chang KY, Yi YW, Kim TK (2006) Small molecule-based reversible reprogramming of cellular lifespan. Nat Chem Biol 2:369–374

    Article  CAS  PubMed  Google Scholar 

  • Won J, Kim M, Kim N, Ahn JH, Lee WG, Kim SS, Chang KY, Yi YW, Kim TK (2008) Retraction: small molecule–based reversible reprogramming of cellular lifespan. Nat Chem Biol 4:431. retracted 17 June 2008

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Wang Y, Jiang W, Liu X, Dubois RL, Lin C-S, Ludwig T, Bakkenist CJ, Zha S (2012) Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. J Cell Biol 198:305–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang H, Rudge DG, Koos JD, Vaidialingham B, Yang HJ, Pavletich NP (2013) mTOR kinase structure, mechanism and regulation. Nature 497:217–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao S-L, Akhtar AJ, McKenna KA, Bedi GC, David S, Mack M, Rajani R, Collector MI, Jones RJ, Sharkis SJ, Fuchs EJ, Bedi A (1996) Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34 cdc2 kinase. Nat Med 2:1140–1143

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Northern Institute for Cancer Research (NICR), Newcastle University, Newcastle, UK

    Ian Hickson

  2. Oncology IMED Biotech Unit, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK

    Kurt G. Pike & Stephen T. Durant

Authors
  1. Ian Hickson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kurt G. Pike
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen T. Durant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian Hickson .

Editor information

Editors and Affiliations

  1. Vertex Pharmaceuticals (Europe) Ltd, Abingdon, Oxfordshire, United Kingdom

    John Pollard

  2. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola Curtin

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hickson, I., Pike, K.G., Durant, S.T. (2018). Targeting ATM for Cancer Therapy: Prospects for Drugging ATM. In: Pollard, J., Curtin, N. (eds) Targeting the DNA Damage Response for Anti-Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-75836-7_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-75836-7_8

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-75834-3

  • Online ISBN: 978-3-319-75836-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation