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Targeting CHK1 for Cancer Therapy: Rationale, Progress and Prospects

  • David A. Gillespie
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

During the past 20 years or so the serine-threonine protein kinase CHK1 has emerged as a key regulator of genome stability in vertebrate cells. When cells sustain acute DNA damage, or when DNA replication is impeded, CHK1 is activated to mitigate against the lethal consequences of cell division with damaged or incompletely replicated genomes. To achieve this CHK1 acts to delay cell cycle progression, stimulate DNA repair, and to promote the accurate completion of genome duplication. Collectively, these checkpoint responses are crucial for cell survival under conditions of genotoxic stress, and numerous pre-clinical studies have shown that inhibition of CHK1 can enhance tumour cell killing by radiation and genotoxic chemotherapeutic agents with diverse mechanisms of action. As a result, a number of small-molecule CHK1 inhibitor drugs have been developed, some of which have reached clinical trials in combination with existing chemotherapies. CHK1 inhibitors have also been shown to synergise with non-genotoxic inhibitors targeting other checkpoint regulators, such as Wee1 kinase, whilst other evidence suggests that certain tumour cell types may be inherently sensitive to CHK1 inhibition alone, perhaps reflecting underlying defects in DNA repair or replication processes. Despite these promising advances, rational strategies for the targeted deployment of CHK1 inhibitor drugs remain at a relatively early stage of development, whilst the important issues of therapeutic index and normal tissue toxicity remain to be fully explored.

Keywords

Cancer therapy CHK1 DNA damage Checkpoint DNA repair Mitosis Chemotherapy Cell cycle Protein kinase Inhibitor drug 

Notes

Acknowledgements

D.A.G. acknowledges the IMBRAIN Project (FP7-REGPOT-2012-CT2012-31637-IMBRAIN: EU FP7 and Gobierno de Canarias) and World Wide Cancer Research Project Grant 12-0149 for financial support.

Conflict of Interest There are no conflicts of interest.

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Biomedical Technologies, Canary Islands Centre for Biomedical Research, Faculty of MedicineUniversity of La LagunaTenerifeSpain

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