Niraparib hydrochloride (MK-4827 hydrochloride) is an inhibitor of poly (ADP-ribose) polymerase (PARP) with potential antineoplastic activity. By inhibiting PARP activity, niraparib hydrochloride increases DNA strand breaks, leading to genomic instability and apoptosis. The PARP family of proteins detects and repairs single-strand DNA breaks via the base-excision repair (BER) pathway.

PARP2:2.1 nM, PARP1:3.8nM

MK-4827 significantly enhances the effectiveness of radiation on human tumor xenografts (whether p53 wild-type or p53 mutant), demonstrating good tolerability in vivo. When used alone, it also exhibits efficacy against BRCA-1 deficient xenograft models.

In cell assays, MK-4827 exhibits inhibitory effects on PARP activity (EC50: 4 nM) and suppresses the proliferation of cancer cells carrying BRCA-1/2 mutations (IC50: 10-100 nM). It effectively inhibits PARP-1/2 (IC50: 3.8/2.1 nM) but shows significantly lower selectivity (over 100-fold) against PARP-3, V-PARP, and tankyrase-1 (IC50: 1300/330/570 nM). In MDA-MB-436 human breast adenocarcinoma cells with a BRCA-1 mutation, MK-4827 has a CC50 of 18 nM; in CAPAN-1 human pancreatic cancer cells with a BRCA-2 deficiency, the CC50 is 90 nM. Normal human prostatic and breast epithelial cells exhibit resistance to MK-4827. This indicates that PARP inhibitors like MK-4827 have selective cytotoxicity in cancer cells with BRCA-1/2 mutations, minimizing the impact on surrounding tissue.