Rucaparib

Rucaparib (AG014699) is an orally active, potent inhibitor of PARP proteins (PARP-1, PARP-2 and PARP-3) with a K_i of 1.4 nM for PARP1. Rucaparib is a modest hexose-6-phosphate dehydrogenase (H6PD) inhibitor. Rucaparib has the potential for castration-resistant prostate cancer (CRPC) research^[1][2][3][4]. In Vitro: Rucaparib (AG014699) is a possible N-demethylation metabolite of AG14644^[1].
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^[2].
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^[5].
Rucaparib inhibits PARP-1 activity by 97.1% at a concentration of 1 μM in permeabilised D283Med cells^[6].
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^[1].
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^[2].
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^[2].
Rucaparib enhances the antitumor activity of temozolomide and indicates complete and sustained tumor regression in NB1691 and SHSY5Y xenografts^[6].