Poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of cancer

The human PARP enzyme family contains 17 members that are divided into five subfamilies, the chief one of which includes the DNA-dependent enzymes (PARP1/2/3). These enzymes participate, inter alia, in DNA repair, transcription, chromatin remodeling, and cells cycle progression. PARP 1/2 catalyze both the mono-ADP ribosylation (MARylation) and poly-ADP ribosylation (PARylation) of its various substrates including itself. PARP1/2 catalyze the formation of large (200 units) linear and branched ADP-ribosyl polymer chains. When the PARP enzyme binds to DNA containing various lesions, it is activated. ADP ribosylated PARPs mark the sites of DNA damage and attract repair proteins. Back-of-the-envelope calculations suggest that the number of single-strand breaks and base loss or modification ranges from 10,000 to 100,000 per cell per day. To function properly, at least in proliferating and germline cells, the DNA lesions must be repaired. Otherwise, cell death may ensue or deleterious mutations that can cause cancer or cell senescence can occur. The FDA has approved four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) for the treatment of ovarian, breast, prostate, and pancreatic cancer. These agents are approved for cancers with homologous-recombination repair deficiencies including BRCA1/2 mutations. These inhibitors are approved agents used for neoadjuvant, adjuvant, and maintenance therapies. The Chinese NMPA has approved three PARP antagonists (fuzuloparib, pamiparib, senaparib) for the treatment of ovarian cancer. All seven of these drugs are orally bioavailable and fall within the criteria of Lipinski's rule of five. Drug resistance develops in most PARP-inhibitor-treated cancer patients within one or two years.