PF-5274857 是一种有效的、选择性的、具有口服活性和可透过血脑屏障的Smo拮抗剂，IC50值为 5.8 nM，Ki值为 4.6 nM。PF-5274857 有潜力用于包括激活的 Hh 途径驱动的脑肿瘤和脑转移在内的多种肿瘤的研究。
| 生物活性 | PF-5274857 is a potent, selective, orally active and brain-penetrant antagonist ofSmo, with anIC50of 5.8 nM andKiof 4.6 nM. PF-5274857 has potential for research of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway[1]. |
| IC50& Target | IC50: 5.8 nM (Smo); Ki: 4.6 nM (Smo)[1] |
体外研究
(In Vitro) | PF-5274857 completely inhibits Shh-induced Hh pathway activity with an IC50of 2.7±1.4 nM measured by the transcriptional activity of Smo downstream gene Gli1 in MEF cells[1].
PF-5274857 shows less than 20% inhibition against a broad panel of protein kinases at 1 μM[1].
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体内研究
(In Vivo) | PF-5274857 (1-30 mg/kg; p.o. once daily for 6 days) shows robust antitumor efficacy and correlation between PK and PD in medulloblastoma allograft mice models[1].
PF-5274857 (10 mg/kg; i.h.) in the plasma is able to cross the blood-brain barrier in rats within 4 hours postdose[1].
PF-5274857 (10-100 mg/kg; p.o. once daily for 4 days) is able to target Smo in the brain leading to the downregulation of Hh pathway activity in the brain tumor[1].
PF-5274857 (30 mg/kg; p.o. once daily for 34 days) increases the survival rates of primary Ptch+/–p53–/–medulloblastoma mice[1].
PF-5274857 (5-30 mg/kg; p.o.) exhibits the apparent volume of distribution of 5.6±0.5 L/kg and the half-life (T1/2) of 1.7±0.1 hours[1].
| Animal Model: | Severe combined immunodeficient (SCID)-beige mice (6-8 weeks old) are genetically engineered[1] | | Dosage: | 0, 1, 5, 10, 30 mg/kg | | Administration: | P.o. once daily for 6 days | | Result: | Showed robust antitumor activity with an in vivo IC50of 8.9±2.6 nM. |
| Animal Model: | Severe combined immunodeficient (SCID)-beige mice (6-8 weeks old)[1] | | Dosage: | 0, 5, 10, 30 mg/kg (Pharmacokinetic Analysis) | | Administration: | A single p.o. | | Result: | The apparent volume of distribution of 5.6±0.5 L/kg; the half-life (T1/2) of 1.7±0.1 hours. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 125 mg/mL(286.07 mM;Need ultrasonic) H2O :< 0.1 mg/mL (ultrasonic;warming;heat to 60℃)(insoluble) 配制储备液 | 1 mM | 2.2885 mL | 11.4427 mL | 22.8854 mL | | 5 mM | 0.4577 mL | 2.2885 mL | 4.5771 mL | | 10 mM | 0.2289 mL | 1.1443 mL | 2.2885 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。-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： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.08 mg/mL (4.76 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.76 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 20.8 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。 2. 请依序添加每种溶剂： 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.08 mg/mL (4.76 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.76 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 20.8 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。 3. 请依序添加每种溶剂： 10% DMSO 90%corn oil Solubility: ≥ 2.08 mg/mL (4.76 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.76 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 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。 *以上所有助溶剂都可在本网站选购。
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