PF-543
(Synonyms: (2R)-1-[[4-[[3-甲基-5-[(苯磺酰基)甲基]苯氧基]甲基]苯基]甲基]-2-吡咯烷甲醇,PF543; PF 543) 目录号 : GC11917
PF-543是一种强效、选择性、可逆和鞘氨醇竞争性SphK 1抑制剂，IC50值为2nM，Ki值为3.6 nM。
Cas No.:1415562-82-1
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
|
Cell experiment [1]: |
|
|
Cell lines |
1483 cells |
|
Preparation method |
PF-543 modulates the levels of endogenous sphingosine and S1P. Lipids were extracted from 1483 cells treated for 1 h at 37℃ in medium lacking serum with a range of concentrations of PF-543(0.01, 0.1, 1, 10, 100, 1000nM). Lipids were quantified using MS |
|
Reaction Conditions |
1 μM；1 h |
|
Applications |
In 1483 cells pretreated for 1h with a range of concentrations of PF-543, PF-543 dose-dependently depleted the intracellular level of S1P with EC50 concentration of 8.4 nM and elevated the intracellular level of sphingosine. PF-543 showed no effect on the growth of several other cancer cell lines. PF-543 inhibited S1P formation in human whole blood (IC50=26.7 nM). |
|
Animal experiment [2]: |
|
|
Animal models |
Mouse hypoxic model of pulmonary hypertension |
|
Preparation method |
Mice were placed into a hypobaric chamber and maintained at 550 mbar atmospheric pressure (~ 10% O2 concentration) for a period of 3 weeks. Every second day mice received an intraperitoneal injection of RB-005, PF-543 (10 mg/kg and 1 mg/kg, respectively) or vehicle (20% (2-Hydroxypropyl)-β-cyclodextrin in PBS). The chamber was depressurized and then repressurised in order to inject the mice . Mice were initially dosed (i.p.) with 10 mg/kg or 30 mg/kg of PF-543 for 24 h. |
|
Dosage form |
i.p.; 10 mg/kg or 30 mg/kg; 24 h |
|
Applications |
In a mouse hypoxic model of pulmonary hypertension, PF-543 showed no effect on vascular remodelling but reduced right ventricular hypertrophy. Administration of 10 mg/kg PF-543 for 24 h to mice decreased SK1 expression in pulmonary vessels. |
|
References: [1] Schnute M E et al. , Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem J. 2012, 444(1): 79-88. [2] MacRitchie N, et al. Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension. Cell Signal. 2016 Aug;28(8):946-55. |
|
PF-543 is a potent, selective, reversible, and sphingosine-competitive inhibitor of SphK1 with an IC50 value of 2nM and a Ki value of 3.6 nM[1]. SphK1 is a kinase that phosphorylates sphingosine to sphingosine-1-phosphate (S1P), which promotes cell growth, survival, and migration, and regulates lymphocyte trafficking. The selectivity of PF-543 for SPHK 1 is over 100 times that of SPHK 2[2]. PF-543 induces apoptosis, necrosis, and autophagy.
In vitro, PF-543 inhibits the formation of C17-S1P in 1483 cells, with an IC50 of 1.0 nM[1]; PF-543 inhibits SphK1 leading to a dose-dependent depletion of intracellular S1P levels, with an EC50 of 8.4 nM and an accompanying increase in intracellular sphingosine levels in 1483 cells[1]; PF-543 (10-1000 nM; 24h) treatment eliminates SK expression in PASM cells[1]. Treatment with 200 nM PF-543 for 1h decreased endogenous S1P levels by tenfold in 1483 cells, with a corresponding increase in sphingosine levels[2]. PF-543 (0.1-10 μM; 24 h) treatment of PASM cells induces caspase-3/7 activity[3].
In vivo, PF-543 (1 mg/kg; intraperitoneal injection; every other day; for 3 weeks) reduces right ventricular hypertrophy in female C57BL/6 J mice, decreases the expression of p53, increases the expression of the antioxidant nuclear factor Nrf-2, but has no effect on vascular remodeling[3]. When mice were initially treated with an intraperitoneal injection of 10 mg/kg or 30 mg/kg PF-543 for 24 h, the blood sample T1/2 was 1.2 h, which could induce a decrease in SK1 expression in the pulmonary vasculature[3].
References:
[1] Schnute M E et al. , Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem J. 2012, 444(1): 79-88.
[2] Hamada M, et al. Induction of autophagy by sphingosine kinase 1 inhibitor PF-543 in head and neck squamous cell carcinoma cells. Cell Death Discov. 2017 Aug 14;3:17047.
[3] MacRitchie N, et al. Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension. Cell Signal. 2016 Aug;28(8):946-55.
PF-543是一种强效、选择性、可逆和鞘氨醇竞争性SphK 1抑制剂，IC50值为2nM，Ki值为3.6 nM[1]。SphK1是一种将鞘氨醇磷酸化为鞘氨醇-1-磷酸（S1P）的激酶，S1P促进细胞生长、存活和迁移，并调节淋巴细胞运输。PF-543对SPHK 1的选择性是SPHK 2的100倍以上[2]。PF-543诱导细胞凋亡、坏死和自噬。
在体外，PF-543 抑制1483细胞中C17-S1P的形成，IC50 of 1.0 nM[1]；PF-543 抑制 SphK1导致细胞内S1P水平的剂量依赖性消耗，EC50 8.4 nM 的浓度和伴随的 1483细胞中鞘氨醇细胞内水平的升高[1]；PF-543 (10-1000 nM；24h) 处理PASM 细胞消除SK表达[1]。200 nM PF-543 处理 1h，1483细胞中的内源性 S1P水平降低了10倍，鞘氨醇水平相应增加[2]。PF-543 (0.1-10 μM；24 h) 处理PASM细胞诱导caspase-3/7 活性[3]。
在体内，PF-543 (1 mg/kg；腹膜内注射；每隔一天；持续3周)会减少雌性C57BL/6 J小右心室肥大，减少p53的表达，增加抗氧化核因子Nrf-2的表达，但对血管重塑没有影响[3]。当小鼠最初被腹膜注射10 mg/kg的PF-543处理24 h，血液样本中的T1/2为1.2 h，可诱导肺血管中 SK1 表达的降低[3]。
| Cas No. | 1415562-82-1 | SDF | |
| 别名 | (2R)-1-[[4-[[3-甲基-5-[(苯磺酰基)甲基]苯氧基]甲基]苯基]甲基]-2-吡咯烷甲醇,PF543; PF 543 | ||
| 化学名 | [(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol | ||
| Canonical SMILES | CC1=CC(=CC(=C1)OCC2=CC=C(C=C2)CN3CCCC3CO)CS(=O)(=O)C4=CC=CC=C4 | ||
| 分子式 | C27H31NO4S | 分子量 | 465.6 |
| 溶解度 | ≥ 23.3 mg/mL in DMSO, ≥ 51 mg/mL in EtOH with ultrasonic and warming | 储存条件 | Store at -20°C |
| General tips | 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°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.1478 mL | 10.7388 mL | 21.4777 mL |
| 5 mM | 0.4296 mL | 2.1478 mL | 4.2955 mL |
| 10 mM | 0.2148 mL | 1.0739 mL | 2.1478 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。