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Targeting ATM for Cancer Therapy: Prospects for Drugging ATM

  • Ian Hickson
  • Kurt G. Pike
  • Stephen T. Durant
Chapter
Part of the Cancer Drug Discovery and Development book series (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.

Keywords

DDR Ataxia-telangiectasia mutated ATM ATM inhibitor AZ31 AZ32 AZD0156 AZD1390 KU-58050 KU-55933 KU-59403 KU-60019 CP-466722 

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ian Hickson
    • 1
  • Kurt G. Pike
    • 2
  • Stephen T. Durant
    • 2
  1. 1.Northern Institute for Cancer Research (NICR)Newcastle UniversityNewcastleUK
  2. 2.Oncology IMED Biotech Unit, Innovative Medicines and Early DevelopmentAstraZenecaCambridgeUK

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