1. Metabolic Enzyme/Protease
  2. Phosphodiesterase (PDE)
  3. PF-8380

PF-8380 是一种有效的 autotaxin 抑制剂,体外酶实验和人类全血细胞实验中,IC50 分别为 2.8 nM 和 101 nM。

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PF-8380 Chemical Structure

PF-8380 Chemical Structure

CAS No. : 1144035-53-9

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10 mM * 1 mL in DMSO ¥550
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1 mg ¥290
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5 mg ¥500
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10 mg ¥800
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25 mg ¥1700
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50 mg ¥2800
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100 mg ¥4500
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Top Publications Citing Use of Products

    PF-8380 purchased from MCE. Usage Cited in: J Clin Invest. 2017 Apr 3;127(4):1517-1530.  [Abstract]

    Western blot analysis demonstrate decreased expression of dephosphorylated NFAT1 and total and active β-catenin proteins in allografts treated with PF-8380 (n = 4/group). All representative blots shown are from the same biological samples. Total and active β-catenin are blotted simultaneously on 2 parallel gels.
    • 生物活性

    • 实验参考方法

    • 纯度 & 产品资料

    • 参考文献

    生物活性

    PF-8380 is a potent autotaxin inhibitor with an IC50 of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood.

    IC50 & Target[1]

    Autotaxin

    2.8 nM (IC50, In isolated enzyme assay)

    体外研究
    (In Vitro)

    PF-8380 also inhibits rat autotaxin with an IC50 of 1.16 nM with FS-3 substrate. Potency of PF-8380 is maintained when using enzyme produced from fetal fibroblasts used in combination with lysophosphatidyl choline (LPC) as a substrate. In human whole blood incubated with PF-8380 for 2 h, autotaxin is inhibited with an IC50 of 101 nM[1]. Autotaxin (ATX), an enzyme with lysophospholipase D (lysoPLD) activity, catalyzes the production of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Pre-treatment of GL261 and U87-MG cells with 1 μM PF-8380 followed by 4 Gy irradiation results in decreased clonogenic survival, decreases migration (33% in GL261; P=0.002 and 17.9% in U87-MG; P=0.012), decreases invasion (35.6% in GL261; P=0.0037 and 31.8% in U87-MG; P=0.002), and attenuates radiation-induced Akt phosphorylation[2].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    体内研究
    (In Vivo)

    The pharmacokinetic profile of PF-8380 is evaluated at an intravenous dose of 1 mg/kg and oral doses of 1 to 100 mg/kg out to 24 h. PF-8380 has mean clearance of 31 mL/min/kg, volume of distribution at steady state of 3.2 L/kg, and effective t1/2 of 1.2 h. Oral bioavailability is moderate, ranging from 43 to 83%. Plasma concentrations increased with single oral escalating doses, but Cmax increased at a rate that is approximately proportional to dose from 1 to 10 mg/kg and less than proportional to dose from 10 to 100 mg/kg. PF-8380 exposures estimated by area under the curve are approximately proportional to dose and linear up to 100 mg/kg. Plasma C16:0, C18:0, and C20:0 LPA levels are measured immediately after collection. Maximal reduction of LPA levels is observed by the 3 mg/kg dose at 0.5 h with all LPA returning at or above baseline at 24 h[1]. Treatment with 10 mg/kg PF-8380 increases tumor-associated vascularity modestly by 20% (P=0.497). When compared to control, treatment of PF-8380 45 min before 4 Gy irradiation decreases vascularity by nearly 48% when compared to control (P=0.031) and by 65% when compared to mice that received radiation alone (P=0.011)[2].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    分子量

    478.33

    Formula

    C22H21Cl2N3O5

    CAS 号
    性状

    固体

    颜色

    White to light brown

    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 2 years
    -20°C 1 year
    溶解性数据
    In Vitro: 

    DMSO 中的溶解度 : 100 mg/mL (209.06 mM; 超声助溶; 吸湿的 DMSO 对产品的溶解度有显著影响,请使用新开封的 DMSO)

    配制储备液
    浓度 溶剂体积 质量 1 mg 5 mg 10 mg
    1 mM 2.0906 mL 10.4530 mL 20.9061 mL
    5 mM 0.4181 mL 2.0906 mL 4.1812 mL
    查看完整储备液配制表

    * 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, 2 years; -20°C, 1 year。-80°C储存时,请在2年内使用, -20°C储存时,请在1年内使用。

    • 摩尔计算器

    • 稀释计算器

    Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

    质量
    =
    浓度
    ×
    体积
    ×
    分子量 *

    Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

    This equation is commonly abbreviated as: C1V1 = C2V2

    浓度 (start)

    C1

    ×
    体积 (start)

    V1

    =
    浓度 (final)

    C2

    ×
    体积 (final)

    V2

    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

    • 方案 一

      请依序添加每种溶剂: 10% DMSO    40% PEG300    5% Tween-80    45% Saline

      Solubility: ≥ 0.67 mg/mL (1.40 mM); 澄清溶液

      此方案可获得 ≥ 0.67 mg/mL(饱和度未知)的澄清溶液。

      1 mL 工作液为例,取 100 μL 6.7 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;再向上述体系中加入 50 μL Tween-80,混合均匀;然后再继续加入 450 μL 生理盐水 定容至 1 mL

      生理盐水的配制:将 0.9 g 氯化钠,溶解于 ddH₂O 并定容至 100 mL,可以得到澄清透明的生理盐水溶液。
    • 方案 二

      请依序添加每种溶剂: 10% DMSO    90% (20% SBE-β-CD in Saline)

      Solubility: ≥ 0.67 mg/mL (1.40 mM); 澄清溶液

      此方案可获得 ≥ 0.67 mg/mL(饱和度未知)的澄清溶液。

      1 mL 工作液为例,取 100 μL 6.7 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液 中,混合均匀。

      20% SBE-β-CD in Saline 的配制(4°C,储存一周):2 g SBE-β-CD(磺丁基醚 β-环糊精)粉末定容于 10 mL 的生理盐水中,完全溶解至澄清透明。

    以下溶解方案,请直接配置工作液。建议现用现配,在短期内尽快用完。 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。

    • 方案 一

      请依序添加每种溶剂: 50% PEG300    50% Saline

      Solubility: 10 mg/mL (20.91 mM); 悬浊液; 超声助溶

    动物溶解方案计算器
    请输入动物实验的基本信息:

    给药剂量

    mg/kg

    动物的平均体重

    g

    每只动物的给药体积

    μL

    动物数量

    由于实验过程有损耗,建议您多配一只动物的量
    请输入您的动物体内配方组成:
    %
    DMSO +
    +
    %
    Tween-80 +
    %
    Saline
    如果您的动物是免疫缺陷鼠或者体弱鼠,建议 DMSO 中的在最后工作液体系中的占比尽量不超过 2%。
    方案所需 助溶剂 包括:DMSO ,均可在 MCE 网站选购。 Tween 80,均可在 MCE 网站选购。
    计算结果
    工作液所需浓度 : mg/mL
    储备液配制方法 : mg 药物溶于 μL  DMSO(母液浓度为 mg/mL)。
    您所需的储备液浓度超过该产品的实测溶解度,以下方案仅供参考,如有需要,请与 MCE 中国技术支持联系。
    动物实验体内工作液的配制方法 : 取 μL DMSO 储备液,加入 μL  μL ,混合均匀至澄清,再加 μL Tween 80,混合均匀至澄清,再加 μL 生理盐水
    连续给药周期超过半月以上,请谨慎选择该方案。
    请确保第一步储备液溶解至澄清状态,从左到右依次添加助溶剂。您可采用超声加热 (超声清洗仪,建议频次 20-40 kHz),涡旋吹打等方式辅助溶解。
    纯度 & 产品资料

    纯度: 99.04%

    参考文献
    Kinase Assay
    [1]

    FS-3 substrate is solubilized in assay buffer at 500 μM and frozen at -20°C in single-use aliquots for up to 4 weeks. Recombinant autotaxin is diluted in Tris-buffered saline (140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 50 mM Tris, pH 8.0) and incubated with compound in DMSO or DMSO alone (final 1% DMSO) for 15 min at 37°C, and the reaction is started with the addition of FS-3 at a final concentration of 1 μM. The reaction is allowed to proceed at 37°C for 30 min and monitored at 520 nm until the uninhibited control compared with a no-enzyme control gave a Z′≥0.5. IC50s are determined in triplicate by using a four-parameter fit[1].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [2]

    HUVEC (1×106) and bEnd.3 cells (1×106) are plated in 100 mm plates and after 24 h, U87-MG (2×106) and GL261 (2×106) cells are plated onto transwell inserts. After co-culture for 24 h, cells are treated with 1 μM of PF-8380 or vehicle control DMSO for 45 min prior to irradiation with 0, 2, 4, 6, or 8 Gy. After the treatments as co-culture with either PF-8380 or DMSO calculated numbers of U87-MG and GL261 cells are plated to enable normalization for plating efficiencies. After 7 to 10 day incubation plates are fixed with 70% EtOH and stained with 1% methylene blue. Colonies consisting of >50 cells are counted by viewing the plates under a microscope. The survival fractions are calculated as (number of colonies/number of cells plated)/(number of colonies for corresponding control/number of cells plated). Survival curves are analyzed by curve fitting to the alpha/beta model calculating D0 and n[2].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1][2]

    Rats[1]
    Male Lewis rats weighing 275 to 300 g are used and acclimated to their surroundings for approximately 1 week with food and water provided ad libitum. A minimum of 1 day before study, animals are anesthetized with isoflurane (to effect) and implanted with Culex vascular catheters in the carotid artery. Animals are acclimated in Culex cages overnight before dosing. Patency of the carotid artery catheter is maintained by using the "tend" function of the Culex automated blood sampler. Animals are dosed with PF-8380 at 1, 3, 10, 30, and 100 mg/kg by oral gavage after an overnight fast. Blood collections are obtained from the carotid artery and performed by the Culex automated blood sampler at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. Blood is centrifuged, and plasma is collected for analysis of PF-8380 and LPA concentrations.
    Mice[2]
    GL261 cells (1×106) are injected into the right hind limb of nude mice. Once tumors are palpable the mice are serpentine sorted into groups of six to seven animals representing similar distributions of tumor sizes (range=240 mm3). Tumor bearing mice are injected intraperitoneally with vehicle (DMSO) or PF-8380 at 10 mg/kg body weight once daily for five consecutive days. Forty five minutes after drug injection, mice are anesthetized with isoflurane and positioned in the RS2000 irradiator. They are then irradiated with 2 Gy daily for five consecutive days for a total of 10 Gy. Lead blocks (10 mm thick) are used to shield the head, thorax, and abdomen. Tumor size is monitored longitudinally using an external traceable digital caliper. Mice are sacrificed by cervical dislocation once the tumors reached a volume of approximately 10 mm3 or when ulceration becomes apparent.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    参考文献

    完整储备液配制表

    * 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, 2 years; -20°C, 1 year。-80°C储存时,请在2年内使用, -20°C储存时,请在1年内使用。

    可选溶剂 浓度 溶剂体积 质量 1 mg 5 mg 10 mg 25 mg
    DMSO 1 mM 2.0906 mL 10.4530 mL 20.9061 mL 52.2652 mL
    5 mM 0.4181 mL 2.0906 mL 4.1812 mL 10.4530 mL
    10 mM 0.2091 mL 1.0453 mL 2.0906 mL 5.2265 mL
    15 mM 0.1394 mL 0.6969 mL 1.3937 mL 3.4843 mL
    20 mM 0.1045 mL 0.5227 mL 1.0453 mL 2.6133 mL
    25 mM 0.0836 mL 0.4181 mL 0.8362 mL 2.0906 mL
    30 mM 0.0697 mL 0.3484 mL 0.6969 mL 1.7422 mL
    40 mM 0.0523 mL 0.2613 mL 0.5227 mL 1.3066 mL
    50 mM 0.0418 mL 0.2091 mL 0.4181 mL 1.0453 mL
    60 mM 0.0348 mL 0.1742 mL 0.3484 mL 0.8711 mL
    80 mM 0.0261 mL 0.1307 mL 0.2613 mL 0.6533 mL
    100 mM 0.0209 mL 0.1045 mL 0.2091 mL 0.5227 mL
    Help & FAQs
    • Do most proteins show cross-species activity?

      Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

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    产品名称:
    PF-8380
    目录号:
    HY-13344
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