PARP Inhibitors

PARP, one of the most abundant proteins in the nucleus, has the principal role in regulating the cellular processes that are most relevant in terms of pathophysiology and experimental therapy. PARP1 which is a 116-kDa protein consists of three main domains is the most important member of the PARP family and can be a DNA-damage sensor and signalling molecule because the ZINC FINGERS of PARP recognize singleand double-stranded DNA breaks. PARP can be cleaved into inactive fragments by caspases or matrix metalloproteinases (MMPs). The phosphorylation of PARP by protein kinase-C (PKC), through the inhibition of its DNA binding, also suppresses PARP activity. PARP, through physical interactions and/or catalytic actions, promotes activator protein-1 (AP1) and nuclear factor-κB (NF-κB)-dependent signal-transduction processes and can suppress the activation of the cytoprotective AKT pathway; therefore, the inhibition of PARP can suppress AP1 and NF-κB activation and induce AKT phosphorylation.