Rucaparib (AG014699) phosphate 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 phosphate 是六磷酸己糖脱氢酶 (H6PD) 抑制剂。Rucaparib phosphate 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) phosphate is an orally active, potent inhibitor ofPARPproteins (PARP-1, PARP-2 and PARP-3) with aKiof 1.4 nM forPARP1. Rucaparib phosphate is a modesthexose-6-phosphate dehydrogenase (H6PD)inhibitor. Rucaparib phosphate has the potential for castration-resistant prostatecancer(CRPC) research[1][2][3][4]. |
| IC50& Target[1][2] | PARP-1 1.4 nM (Ki) | PARP-2 | PARP-3 |
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体外研究
(In Vitro) | Rucaparib (AG014699) phosphate is a possible N-demethylation metabolite of AG14644[1].
Rucaparib (0.1, 1, 10, 100 μM; 24 hours) phosphate 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 phosphate is due to downstream inhibition of activation of NF-κB, and is independent of SSB repair inhibition. Rucaparib phosphate 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 phosphate 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) phosphate and AG14584 significantly increase Temozolomide toxicity. Rucaparib (1 mg/kg) phosphate significantly increases Temozolomide-induced body weight loss. Rucaparib (0.1 mg/kg) phosphate 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) phosphate 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) phosphate has greatest antitumor effect with three complete regressions[2].
Rucaparib phosphate 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 | 4°C, sealed storage, away from moisture *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) |
| 溶解性数据 | In Vitro: DMSO : ≥ 33 mg/mL(78.32 mM) H2O : 5 mg/mL(11.87 mM;ultrasonic and warming and heat to 60℃) *"≥" means soluble, but saturation unknown. 配制储备液 | 1 mM | 2.3733 mL | 11.8663 mL | 23.7327 mL | | 5 mM | 0.4747 mL | 2.3733 mL | 4.7465 mL | | 10 mM | 0.2373 mL | 1.1866 mL | 2.3733 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month (sealed storage, away from moisture)。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂： ——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂： 5% DMSO 40%PEG300 5%Tween-80 50% saline Solubility: ≥ 2.5 mg/mL (5.93 mM); Clear solution 2. 请依序添加每种溶剂： 5% DMSO 95% (20%SBE-β-CDin saline) Solubility: ≥ 2.5 mg/mL (5.93 mM); Clear solution 3. 请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.17 mg/mL (5.15 mM); Clear solution
此方案可获得 ≥ 2.17 mg/mL (5.15 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 21.7 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。 4. 请依序添加每种溶剂： 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.17 mg/mL (5.15 mM); Clear solution
此方案可获得 ≥ 2.17 mg/mL (5.15 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 21.7 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。 5. 请依序添加每种溶剂： 10% DMSO 90%corn oil Solubility: ≥ 2.17 mg/mL (5.15 mM); Clear solution
此方案可获得 ≥ 2.17 mg/mL (5.15 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例，取 100 μL 21.7 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。 6. 请依序添加每种溶剂： 1% DMSO 99% saline Solubility: ≥ 0.5 mg/mL (1.19 mM); Clear solution *以上所有助溶剂都可在本网站选购。
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