PF-8380 |
| رقم الكتالوجGC14510 |
An inhibitor of autotaxin
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1144035-53-9
Sample solution is provided at 25 µL, 10mM.
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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.
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].
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].
References:
[1]. Gierse J, et al. A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation. J Pharmacol Exp Ther. 2010 Jul;334(1):310-7.
[2]. Bhave SR, et al. Autotaxin Inhibition with PF-8380 Enhances the Radiosensitivity of Human and Murine Glioblastoma Cell Lines. Front Oncol. 2013 Sep 17;3:236.
[3]. Cao P, et al. Autocrine lysophosphatidic acid signaling activates β-catenin and promotes lung allograft fibrosis. J Clin Invest. 2017 Apr 3;127(4):1517-1530.
| Cell experiment [1]: | |
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Cell lines |
Mouse glioma GL261 cell lines, Human glioblastoma (U87-MG) cells |
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Preparation method |
Soluble in DMSO > 20.9mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
1 μM, 45min |
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Applications |
Pre-treatment of GL261 and U87-MG cells with 1mM PF-8380 followed by 4 Gy irradiation resulted in decreased clonogenic survival, decreased migration, decreased invasion, and attenuated radiation-inducedAkt(protein kinase B) phosphorylation. |
| Animal experiment [2]: | |
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Animal models |
Female Lewis rats |
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Dosage form |
10, 30, 100 mg/kg, b.i.d, oral administration |
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Application |
The specific inhibitor PF-8380 provided >95% reduction in both plasma and air pouch LPA (lysophosphatidic acid), indicating autotaxin is a major source of LPA during inflammation. PF-8380 reduced inflammatory hyperalgesia with the similiar efficacy as naproxen. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Bhave SR1, Dadey D, et al, Autotaxin Inhibition with PF-8380 Enhances the Radiosensitivity of Human and Murine Glioblastoma Cell Lines. Front Oncol. 2013 Sep 17;3:236. doi: 10.3389/fonc.2013.00236. eCollection 2013. [2]. Gierse J1, Thorarensen A, et al, A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation. J Pharmacol Exp Ther. 2010 Jul;334(1):310-7. doi: 10.1124/jpet.110.165845. Epub 2010 Apr 14. | |
| Cas No. | 1144035-53-9 | SDF | |
| Chemical Name | 3,5-dichlorobenzyl 4-(3-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propyl)piperazine-1-carboxylate | ||
| Canonical SMILES | ClC1=CC(COC(N2CCN(CCC(C(C=C3)=CC(O4)=C3NC4=O)=O)CC2)=O)=CC(Cl)=C1 | ||
| Formula | C22H21Cl2N3O5 | M.Wt | 478.33 |
| الذوبان | ≥ 20.9 mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0906 mL | 10.453 mL | 20.9061 mL |
| 5 mM | 0.4181 mL | 2.0906 mL | 4.1812 mL |
| 10 mM | 0.2091 mL | 1.0453 mL | 2.0906 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 30 reference(s) in Google Scholar.)
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