Rucaparib (AG014699) hydrochloride 是一种口服有效的PARP蛋白 (PARP-1, PARP-2 and PARP-3) 抑制剂，对 PARP-1 的Ki为 1.4 nM。Rucaparib hydrochloride 是六磷酸己糖脱氢酶 (H6PD) 抑制剂。Rucaparib hydrochloride 具有用于去势抵抗性前列腺癌 (CRPC) 研究的潜力。
| 生物活性 | Rucaparib (AG014699) hydrochloride is an orally active, potent inhibitor ofPARPproteins (PARP-1, PARP-2 and PARP-3) with aKiof 1.4 nM forPARP1. Rucaparib hydrochloride is a modesthexose-6-phosphate dehydrogenase (H6PD)inhibitor. Rucaparib hydrochloride has the potential for castration-resistant prostatecancer(CRPC) research[1][2][3][4]. |
| IC50& Target | PARP-1 1.4 nM (Ki) | PARP-2 | PARP-3 |
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体外研究
(In Vitro) | 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 LC50being 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].
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体内研究
(In Vivo) | 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 × 107cells 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. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
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