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

  • Junko Murai
  • Yves Pommier
Part of the Cancer Drug Discovery and Development book series (CDD&D, volume 83)


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.


PARP inhibitor Topoisomerase Camptothecin PARP trapping PARP-DNA complex Synthetic lethal Veliparib Niraparib Olaparib Rucaparib Talazoparib 


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA

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