Description
Niraparib tosylate (MK-4827 tosylate) is a highly potent and orally bioavailable PARP1 and PARP2 inhibitor with an IC50 of 3.8 and 2.1 nM, respectively; with significant activity in cancer cells with mutant BRCA-1 and BRCA-2; >330-fold selective against PARP3, V-PARP, and Tank1. Niraparib tosylate leads to inhibition of repair of DNA damage, activates apoptosis, and shows anti-tumor activity.
in vitro
In a whole-cell assay, Niraparib (MK-4827) tosylate hydrate inhibits PARP activity with EC50=4 nM and EC90=45 nM. Niraparib tosylate hydrate inhibits the proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Niraparib tosylate hydrate displays excellent PARP 1 and 2 inhibition with IC50=3.8 and 2.1 nM, respectively, and in a whole-cell assay.
Niraparib tosylate hydrate 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.
in vivo
Niraparib (MK-4827) is well tolerated and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. Niraparib (MK-4827) is well tolerated in vivo and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. Niraparib (MK-4827) is characterized by acceptable pharmacokinetics in rats with plasma clearance of 28 (mL/min)/kg, very high volume of distribution (Vdss=6.9 L/kg), long terminal half-life (t1/2=3.4 h), and excellent bioavailability, F=65%[1].
Niraparib (MK-4827) 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].
References
[1] PHILIP JONES*. Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors[J]. Journal of Medicinal Chemistry, 2009, 52 22: 7170-7185. DOI:
10.1021/jm901188v[2] YUAN YUAN. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP.[J]. Journal of Hematology & Oncology, 2011, 4: 16. DOI:
10.1186/1756-8722-4-16[3] LI WANG. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation.[J]. Investigational New Drugs, 2012: 2113-2120. DOI:
10.1007/s10637-011-9770-x[4] MIRZA M, MONK B, HERRSTEDT J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer.[J]. The New England Journal of Medicine, 2016, 75 1: 0. DOI:
10.1056/nejmoa1611310
