Niraparib, Free Base

Soluble in DMSO. Niraparib, also known as MK-4827, is a poly(ADP-ribose)polymerase (PARP) inhibitor. Niraparib displayed excellent PARP 1 and 2 inhibition with IC50 values of 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with an IC50 of 4 nM, and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2, with IC50 values of 10-100 nM. Niraparib was well tolerated in vivo and showed antitumor activity as a single agent in a xenograft model of BRCA-1 deficient cancer. Jones P., et al. '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. Med. Chem. 52: 7170-7185 (2009). Niraparib enhanced radiation-induced cytotoxicity in neuroblastoma cells. In vivo treatment with niraparib and radiation prolonged survival of mice in a murine xenograft model of metastatic neuroblastoma when compared to single modalities. Mueller S., et al. 'Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a novel therapy for metastatic neuroblastoma.' Anticancer Res. 33: 755-762 (2013). A phase 1 clinical trial demonstrated niraparib inhibited PARP more than 50% at doses greater than 80 mg/day and had antitumour activity at doses beyond 60 mg/day. Antitumour activity of niraparib was reported in BRCA1 or BRCA2 mutation carriers with ovarian cancer, breast cancer, and in patients with sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. Sandhu S.K., et al. 'The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.' Lancet Oncol. 14: 882-892 (2013).