creative-bioarray

Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that mediate the ADP-ribosylation post-translational modification with the substrate NAD⁺. These enzymes play critical roles in the regulation of DNA damage response (DDR), chromatin structure and transcriptional regulation. The 17 members of the human PARP family are evolutionarily conserved in their catalytic domains but have distinct regulatory domains leading to varied biology and the ability to target select members therapeutically. The pharmacological obstruction of PARP1/2 impairs single-strand break DNA repair mechanisms which leads to synthetic lethality specifically in cancers with defective homologous recombination such as BRCA-mutated tumors and has created PARP inhibitors as effective cancer treatments. Other PARPs, such as tankyrases (PARP5a/5b), which regulate Wnt/β-catenin signaling and cell proliferation, have expanded the druggable PARP target space. Drug candidate assessment requires both catalytic inhibition and PARP–DNA trapping along with target engagement inside cells to predict in vivo activity and toxicology properly.