Inhibitors of PARP: Number crunching and structure gazing

Selective inhibitors of PARP1 and PARP2 (PARP1/2) are used to treat cancer patients with deficiencies in the repair of DNA via homologous recombination. Here we provide a perspective on the reported potencies of the most studied of these inhibitors (olaparib, talazoparib, niraparib, rucaparib, and veliparib) in vitro and in vivo and how these numbers relate to the known structures of these inhibitors bound to the active sites of PARP1 and PARP2. We suggest that the phenomenon of PARP trapping is primarily due to the inhibition of the catalytic activity of PARP1 and that the basis for the higher potency of talazoparib compared to the other inhibitors lies in its more extensive network of interactions with conserved residues in the active site. We also consider the potential role of the recently characterized protein “Histone PARylation Factor 1” (HPF1), which interacts with PARP1/2 to form a shared active site, for the design of the next generation of inhibitors of PARP1/2.