Fig. 5

Paradigm shift in the development of PARP inhibitors. a Cytotoxic mechanisms of PARP inhibitors. PARP inhibitors could disrupt catalytic activity as well as cause PARP trapping on DNA, both leading to unrepaired cytotoxic DNA damage accumulation. b Higher therapeutic index of PARP1 selective inhibitors diversified combo opportunities. The reduced hematological toxicities of next-generation PARP1 selective inhibitors may warrant combinations with chemotherapy, while drugs with nonoverlapped toxicities may be better combo choice for first-generation PARP inhibitors. AUC: area under curve. c Chemical structures of 6 launched first-generation PARP inhibitors: olaparib, rucaparib, niraparib, talazoparib, fluzoparib and pamiparib. d PARP1 selective inhibitors AZD5305 and AZD9574