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Poly(ADP-ribose) polymerase inhibition: past, present and future

Nature Reviews Drug Discovery volume 19, pages 711–736 (2020)Cite this article

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Abstract

The process of poly(ADP-ribosyl)ation and the major enzyme that catalyses this reaction, poly(ADP-ribose) polymerase 1 (PARP1), were discovered more than 50 years ago. Since then, advances in our understanding of the roles of PARP1 in cellular processes such as DNA repair, gene transcription and cell death have allowed the investigation of therapeutic PARP inhibition for a variety of diseases — particularly cancers in which defects in DNA repair pathways make tumour cells highly sensitive to the inhibition of PARP activity. Efforts to identify and evaluate potent PARP inhibitors have so far led to the regulatory approval of four PARP inhibitors for the treatment of several types of cancer, and PARP inhibitors have also shown therapeutic potential in treating non-oncological diseases. This Review provides a timeline of PARP biology and medicinal chemistry, summarizes the pathophysiological processes in which PARP plays a role and highlights key opportunities and challenges in the field, such as counteracting PARP inhibitor resistance during cancer therapy and repurposing PARP inhibitors for the treatment of non-oncological diseases.

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Fig. 1: PARylation, PAR removal and the structure of PARP1.
Fig. 2: Selected preclinical PARP research milestones.
Fig. 3: Molecular mechanisms of the anticancer effects of PARP inhibitors.
Fig. 4: PARP inhibition in treating non-oncological diseases.

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Acknowledgements

The research of N.J.C. in the field of PARP has been supported by grants from Cancer Research UK, Cancer Research UK Development Committee, the Association for International Cancer Research (06-0031), the Biotechnology and Biological Sciences Research Council, the Bone Cancer Research Trust, the JGW Patterson Foundation, Newcastle Healthcare Charity, the Northern Cancer Care & Research Society, the Academy of Medical Sciences (NIF\R1\181894) and the UK–India Education and Research Initiative/British Council (DST/INT/UK/P-134/2016). The research of C.S. in the field of PARP is supported by grants from the Swiss National Foundation (31003A_179434) and the Swiss State Secretariat for Education, Research and Innovation (SMG1927).

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  1. Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK

    Nicola J. Curtin

  2. Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland

    Csaba Szabo

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Correspondence to Nicola J. Curtin or Csaba Szabo.

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C.S. has no conflicts of interest to declare. N.C. has served on the scientific advisory boards of various companies making PARP inhibitors (AbbVie, BioMarin, Eisai and Tesaro) and other DNA damage response inhibitors (Sierra). She has received royalty payments from the commercial development of Rubraca, which have been used to fund her group’s research and to establish the Curtin PARP (Passionate About Realizing your Potential) Fund at the Community Foundation (UK). Her PARP-related work has been supported by funding from Agouron Pharmaceuticals, Pfizer, Clovis, BioMarin and BiPar Sciences.

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Curtin, N.J., Szabo, C. Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat Rev Drug Discov 19, 711–736 (2020). https://doi.org/10.1038/s41573-020-0076-6

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