Niraparib (MK-4827)

Xenograft model of BRCA-1 deficient cancer

(S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

0-5 mM

100 mg/kg q.d. or 50 mg/kg b.i.d

3.8 nM, 3.8 nM, 3.8 nM, 3.8 nM, 3.8 nM, 3.8 nM

MK-4827 is well tolerated in vivo and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. [1] In addition, MK-4827 strongly enhances the effect of radiation on a variety of human tumor xenografts, both p53 wild type and p53 mutant. The enhancement of radiation response is observed in clinically relevant radiation-dose fractionation schedules. The therapeutic window during which time MK-4827 interacts with radiation lasts for several hours. These biological attributes make translation of this therapeutic combination treatment feasible for translation to the treatment of a variety of human cancers. [2]

PARP-1 SPA Assay, Enzyme assay is conducted in buffer containing 25 mM Tris, pH 8.0, 1 mM DTT, 1 mM spermine, 50 mM KCl, 0.01% Nonidet P-40, and 1 mM MgCl2. PARP reactions contains 0.1 uCi [3H] NAD+ (200 000 DPM), 1.5 uM NAD+, 150 nM biotinylated NAD+, 1 ug/mL activated calf thymus, and 1-5 nM PARP-1. Autoreactions utilizing SPA bead-based detection are carried out in 50 uL volumes in white 96-well plates. Compounds are prepared in 11-point serial dilution in 96-well plate, 5 uL/well in 5% DMSO/H2O (10xconcentrated). Reactions are initiated by adding first 35 uL of PARP-1 enzyme in buffer and incubating for 5 min at room temperature and then 10 uL of NAD+ and DNA substrate mixture. After 3 h at room temperature, these reactions are terminated by the addition of 50 uL of streptavidin-SPA beads (2.5 mg/mL in 200 mM EDTA, pH 8). After 5 min, they are counted using a TopCount microplate scintillation counter. IC50 data is determined from inhibition curves at various substrate concentrations.

320, 39

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO