PARP1 inhibitor (next-gen)

PARP1 (poly-ADP-ribose polymerase 1) is an enzyme that detects DNA single-strand breaks and helps recruit the machinery needed to repair them, a process called base excision repair. Cells rely on multiple, overlapping DNA repair pathways to maintain genomic integrity; when one pathway is blocked, others can often compensate. However, tumors that already carry defects in a separate repair pathway, homologous recombination, most notably those with mutated BRCA1 or BRCA2 genes, become critically dependent on PARP1-mediated repair to survive. Blocking PARP1 in this setting causes unrepaired DNA damage to accumulate until the cell dies, a concept known as synthetic lethality. Earlier PARP inhibitors block both PARP1 and its close relative PARP2, and also inhibit PARP2 in normal bone marrow, contributing to blood cell toxicities. Next-generation PARP1-selective inhibitors are designed to spare PARP2, aiming to preserve the tumor-killing synthetic lethality while reducing toxicity in healthy tissues that depend on PARP2 for their own repair needs. This class is relevant to cancers with homologous recombination deficiency, including certain breast, ovarian, prostate, and pancreatic tumors, where selectively targeting PARP1 could broaden the population able to tolerate durable treatment while maintaining anti-tumor activity.