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Classification of PARP Inhibitors Based on PARP Trapping and Catalytic Inhibition, and Rationale for Combinations with Topoisomerase I Inhibitors and Alkylating Agents

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PARP Inhibitors for Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 83))

Abstract

All PARP inhibitors in clinical development (veliparib, olaparib, niraparib, rucaparib, talazoparib) are potent submicromolar competitive NAD+ inhibitors for PARP1 and PARP2, thereby blocking PARylation reactions [i.e. formation of poly(ADPribose) polymers]. In addition, PARP trapping, which determines the anticancer activity of PARP inhibitors as single agents, is drug-specific, and PARP inhibitors can be ranked according to their PARP trapping potency: Talazoparib >> niraparib ˜ olaparib ˜ rucaparib > veliparib. The highly synergistic effects of PARP inhibitors in combination with alkylating agent (temozolomide or methyl methanesulfonate, MMS) and topoisomerase I (Top1) inhibitors (camptothecins and indenoisoquinolines) are well documented. Both classes of drugs induce DNA single-strand breaks sensed by PARP. Yet, the molecular mechanisms of synergy are different. For alkylating agents (temozolomide and MMS), both PARP trapping and PARylation inhibition account for the synergy, whereas for Top1 inhibitors, there is no involvement of PARP trapping and it is PARylation inhibition that deters the coupling of PARP with the repair enzyme, tyrosyl-DNA phosphodiesterase TDP1. In this chapter, we will review the differences between PARP inhibitors and the rationale for choosing among different PARP inhibitors in combination with alkylating agents or Top1 inhibitors.

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Authors and Affiliations

  1. Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA

    Junko Murai & Yves Pommier

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  1. Junko Murai
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  2. Yves Pommier
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Correspondence to Yves Pommier .

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Editors and Affiliations

  1. Northern Institute for Cancer Research and Newcastle University Institute for Ageing Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola J. Curtin

  2. CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom

    Ricky A. Sharma

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Murai, J., Pommier, Y. (2015). Classification of PARP Inhibitors Based on PARP Trapping and Catalytic Inhibition, and Rationale for Combinations with Topoisomerase I Inhibitors and Alkylating Agents. In: Curtin, N., Sharma, R. (eds) PARP Inhibitors for Cancer Therapy. Cancer Drug Discovery and Development, vol 83. Humana Press, Cham. https://doi.org/10.1007/978-3-319-14151-0_10

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  • DOI: https://doi.org/10.1007/978-3-319-14151-0_10

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