Rucaparib hydrochloride, also known as AG014699, is a powerful and orally active compound that inhibits PARP proteins including PARP-1, PARP-2, and PARP-3 with a Ki value of 1.4 nM for PARP1. Additionally, Rucaparib hydrochloride acts as a modest inhibitor of hexose-6-phosphate dehydrogenase (H6PD). This compound shows potential in research for castration-resistant prostate cancer (CRPC) [1] [2] [3] [4].
体外活性
Rucaparib (AG014699) hydrochloride is a possible N-demethylation metabolite of AG14644 [1]. Rucaparib (0.1, 1, 10, 100 μM; 24 hours) hydrochloride is cytotoxic and has the LC 50 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 hydrochloride is due to downstream inhibition of activation of NF-κB, and is independent of SSB repair inhibition. Rucaparib hydrochloride 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 hydrochloride inhibits PARP-1 activity by 97.1% at a concentration of 1 μM in permeabilised D283Med cells [6].
体内活性
Rucaparib (AG014699) hydrochloride and AG14584 significantly increase Temozolomide toxicity. Rucaparib (1 mg/kg) hydrochloride significantly increases Temozolomide-induced body weight loss. Rucaparib (0.1 mg/kg) hydrochloride 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) hydrochloride 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) hydrochloride has greatest antitumor effect with three complete regressions [2]. Rucaparib (1 mg/kg; i.p.; daily for 5d) hydrochloride enhances the antitumor activity of temozolomide and indicates complete and sustained tumor regression in NB1691 and SHSY5Y xenografts [6]. Animal Model: Female athymic nude mice, implanted SW620 colorectal tumor cells (1 × 10 7 cells per animal) s.c. [1] Dosage: 0.1 mg/kg in combination with Temozolomide (p.o., 200 mg/kg), 0.05, 0.15, and 0.5 mg/kg in combination with Temozolomide (p.o., 68 mg/kg) or 10 mg/kg Administration: IP, single dose for 0.1 mg/kg and 10 mg/kg, five daily doses for 0-0.5 mg/kg Result: Significantly increased Temozolomide toxicity, showed outstanding chemosensitization potency and caused enhancement of Temozolomide-induced tumor growth delay. Animal Model: CD-1 nude mice bearing established Capan-1 xenografts [2] Dosage: 10 mg/kg or 50, 100 and 150 mg/kg Administration: IP for 10 mg/kg; PO for 50, 100 and 150 mg/kg, single dose (Pharmacokinetics) Result: Parent drug was detectable in the plasma only at 30 min after 10 mg/kg i.p and up to 4 h for 50–150 mg/kg p.o.. Was still detectable in most mice receiving oral rucaparib at 3 days. Does not easily cross the plasma membrane. Animal Model: CD-1 nude mice bearing established Capan-1 xenografts [2] Dosage: 10 mg/kg i.p. daily for 5 days per week for 6 weeks, 50 or 150 mg/kg p.o. daily × five weekly × six, 150 mg/kg p.o. once per week for 6 weeks or three times per week for 6 weeks, or 150 mg/kg p.o. daily for five days every 3 weeks Administration: IP or PO Result: 10 mg/kg i.p. significantly inhibited the growth of the tumor, daily oral administration at 150 mg/kg had an equivalent effect on tumor growth to 10 mg/kg i.p.. The schedule with the greatest antitumor effect was oral administration of 150 mg/kg on a once weekly schedule with three complete regressions. Animal Model: CD-1 nude mice, NB1691 and SHSY5Y xenografts [6] Dosage: 1 mg/kg Administration: IP, daily for 5 d in combination with Temozolomide (orally daily ×5 at a dose of 68 mg/kg) Result: Enhanced the antitumor activity of Temozolomide and indicated complete and sustained tumor regression.
