Niraparib

Niraparib is a potent and selective inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2. PARPs play an important role in DNA repair. They recognize and repair cellular DNA damage, such as single-strand breaks (SSBs) and double-strand breaks (DSBs). Different DNA repair pathways exist to repair these DNA damages, including the base excision repair (BER) pathway for SSBs and BRCA-dependent homologous recombination for DSBs. If BER is impaired, SSBs accumulate and become DSBs, forcing cells to rely on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining, to repair DNA damages. However, some cells can have defective or deficient HR resulting from specific mutations in DNA repair genes, such as BRCA1 and 2. Inhibiting PARPs in the presence of HR deficiency leads to a phenomenon called 'synthetic lethality,' whereby the PARP inhibitor impedes BER, leading to genetic instability and cell death.

Selectivity towards PARP-1 and PARP-2 is 100-fold higher than for other PARP family members. Niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death.