Rucaparib

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; inhibits PARP-1 activity by 97.1% at a concentration of 1 μM in permeabilised D283Med cells; enhances the antitumor activity of temozolomide and indicates complete and sustained tumor regression in NB1691 and SHSY5Y xenografts.Ovarian Cancer Approved(In Vitro):Rucaparib (AG014699) is a possible N-demethylation metabolite of AG14644.Rucaparib (0.1, 1, 10, 100 μM; 24 hours) is cytotoxic and has the LC50 being 5 μM in Capan-1 (BRCA2 mutant) cells and only 100 nM in MX-1 (BRCA1 mutant) cells.The radio-sensitization by Rucaparib is due to downstream inhibition of activation of NF-κB, and is independent of SSB repair inhibition. Rucaparib can target NF-κB activated by DNA damage and overcome toxicity observed with classical NF-κB inhibitors without compromising other vital inflammatory functions.Rucaparib inhibits PARP-1 activity by 97.1% at a concentration of 1 μM in permeabilised D283Med cells.(In Vivo):Rucaparib (AG014699) and AG14584 significantly increase Temozolomide toxicity. Rucaparib (1 mg/kg) significantly increases Temozolomide-induced body weight loss. Rucaparib (0.1 mg/kg) results in a 50% increase in the temozolomide-induced tumor growth delay.Rucaparib (10 mg/kg for i.p. or 50, 150 mg/kg for p.o.; daily for 5 days per week for 6 weeks) significantly inhibits the growth of the tumor, and there is one complete tumor regression and two persistent partial regressions.Rucaparib (150 mg/kg; p.o.; once per week for 6 weeks or three times per week for 6 weeks) has greatest antitumor effect with three complete regressions.Rucaparib enhances the antitumor activity of temozolomide and indicates complete and sustained tumor regression in NB1691 and SHSY5Y xenografts.