Niraparib (hydrochloride)

Niraparib hydrochloride (MK-4827 hydrochloride) is a highly potent and orally bioavailable PARP1 and PARP2 inhibitor with IC₅₀s of 3.8 and 2.1 nM, respectively. Niraparib hydrochloride leads to inhibition of repair of DNA damage, activates apoptosis and shows anti-tumor activity^[1][2][3]. IC50 & Target: IC50: 3.8 nM (PARP1), 2.1 nM (PARP2)^[1] In Vitro: Niraparib inhibits PARP activity with EC₅₀=4 nM and EC₉₀=45 nM in a whole cell assay. Niraparib inhibits proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC₅₀ in the 10−100 nM range. Niraparib displays excellent PARP 1 and 2 inhibition with IC₅₀=3.8 and 2.1 nM, respectively, and in a whole cell assay^[1]. To validate that Niraparib inhibits PARP in these cell lines, A549 and H1299 cells are treated with 1 μM Niraparib for various times and measured PARP enzymatic activity using a chemiluminescent assay. The results show that Niraparib inhibits PARP within 15 minutes of treatment reaching about 85% inhibition in the A549 cells at 1 h and about 55% inhibition at 1 h for the H1299 cells^[2]. In Vivo: Niraparib is well tolerated and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. Niraparib is well tolerated in vivo and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. Niraparib is characterized by acceptable pharmacokinetics in rats with plasma clearance of 28 (mL/min)/kg, very high volume of distribution (Vd_ss=6.9 L/kg), long terminal half-life (t_1/2=3.4 h), and excellent bioavailability, F = 65%^[1]. Niraparib enhances radiation response of p53 mutant Calu-6 tumor in both cases, with the single daily dose of 50 mg/kg being more effective than 25 mg/kg given twice daily^[3].