Rucaparib phosphate

2 years -80 in solvent

One or four daily by i.p.

D425Med, D283Med and D384Med cells

0.4 uM

Normal saline

Rucaparib is a potent inhibitor of purified full-length human PARP-1 and shows higher inhibition of cellular PARP in LoVo and SW620 cells. [1] The radio-sensitization by Rucaparib is due to downstream inhibition of activation of NF-kappaB, and is independent of SSB repair inhibition. Rucaparib could target NF-kappaB activated by DNA damage and overcome toxicity observed with classical NF-kappaB inhibitors without compromising other vital inflammatory functions. [2] Rucaparib inhibits PARP-1 activity by 97.1% at a concentration of 1 uM in permeabilised D283Med cells. [3]

3 or 5 days

Medulloblastoma cell lines are seeded in 96-well plates at a density of 1, 103, 3, 103 and 3, 103, respectively. At 24 hours (D384Med) or 48 hours (D283Med and D425Med) after seeding, the cells are exposed to various concentrations of temozolomide in the presence or absence of 0.4 uM Rucaparib. After 3 days (D425Med and D384Med) or 5 days (D283Med) of culture, cell viability is evaluated by a XTT cell proliferation kit assay. Cell growth is expressed as a percentage in relation to DMSO or 0.4 uM Rucaparib-alone controls. The concentration of temozolomide, alone or in combination with Rucaparib that inhibited growth by 50% (GI50) is calculated. The potentiation factor 50 (PF50) is defined as the ratio of the GI50 of temozolomide in the presence of Rucaparib to the GI50 of temozolomide alone.

Rucaparib phosphate is an inhibitor of PARP with Ki of 1.4 nM for PARP1 in a cell-free assay, also showing binding affinity to eight other PARP domains. Phase 3.

Rucaparib is the phosphate salt of AG-14447 and the first PARP inhibitor to be used in clinical trials, combined with temozolomide.