BetaPharma Drug Discovery
BetaPharma Drug Discovery Accelerating Drug Discovery

Poly(ADP-ribose) polymerases (PARPs) are defined as a family of cell signaling enzymes present in eukaryotes, which are involved in poly(ADP-ribosylation) of DNA-binding proteins. The best studied of these enzymes (PARP-1) is involved in the cellular response to DNA damage so that in the event of irreparable DNA damage overactivation of PARP-1 leads to necrotic cell death. Inhibitors of PARP-1 activity in combination with DNA-binding antitumor drugs may constitute a suitable strategy in cancer chemotherapy. When DNA is moderately damaged, PARP-1 participates in the DNA repair process and the cell survives. However, in the case of extensive DNA damage PARP-1 overactivation induces a decrease of NAD+ and ATP levels leading to cell dysfunction or even to necrotic cell death. So, due to PARP-1 involvement in cell death, pharmacological inhibition of PARP-1 activity by PARP-1 inhibitors may constitute a suitable target to enhance the activity of antitumor drugs through inhibition of necrosis and activation of apoptosis. Mice lacking PARP-1 develop normally and PARP-1–/– fibroblasts and lymphoid cells display a normal apoptotic response after treatment with various apoptotic inducers, such as anti-Fas antibody, TNF-α, γ-radiation, and dexamethasone, which demonstrates that PARP-1 per se is dispensable for apoptosis, at least in these cell types . However, inactivation of PARP-1 by chemical inhibitors and genetic means protects mice from endotoxic shock and other disease models related to inflammation, such as diabetes, stroke, and myocardial reperfusion. In addition, PARP inhibitors protect rats from renal and intestinal ischemia reperfusion– induced (I/R-induced) lethality and tissue injury .