Poly (ADP-ribose) Polymerase (PARP) Inhibitors
Poly (ADP-ribose) polymerases (PARPs) belong to a large protein family (18 putative members to date) functioning in two oppositely directed cellular processes: DNA repair for cell survival and programmed cell death. They function as efficient single strand DNA-break sensors in the first line of defense to protect the genome and control downstream signaling events vital for cell survival. PARP-1, the most-extensively studied member of this family on one hand synthesizes a linear or branched chain of ADP-ribose on various nuclear proteins (typically chromatin-associated which in some cases results in epigenetic modification) or itself. Both auto- and hetero-Ribosylation by PARP eventually lead to the survival of injured proliferating cells. PARP-mediated DNA repair capability also determines mammalian longevity which makes these proteins interesting for human aging studies. On the other hand, PARP-1 is involved in the initiation of the inflammatory response via NF-KB activation and increasing cellular sensitivity to oxygen radicals produced during inflammation resulting in DNA damage, ATP depletion and programmed cell death. In a Caspase-dependent manner, PARP-1 stimulates release of the mitochondrial apoptosis-inducing factor (AIF) and once AIF has migrated into the nucleus, PARP enzymes function in cell death. This unique dual modality drives an intense industrial incentive to develop potent chemical inhibitors of PARPs for the treatment of cancer, stroke, myocardial infarction and long-term neurodegenerative diseases. Several PARP inhibitors are in Phase II (Olaparib, Veliparib, Rucaparib, CEP 9722) and Phase I (MK4827, BMN673) clinical trials. BioVision offers a growing list of PARP inhibitors in its effort to help advance our understanding of PARP biology.