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Purity: ≥98%
PF-8380 is a novel, potent and specific autotaxin (ATX) inhibitor with an IC50 of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has good oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy. Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis.
| ln Vitro |
Additionally, PF-8380 inhibits rat autotaxin, a substrate for FS-3, with an IC50 of 1.16 nM. When fetal fibroblast-produced enzymes were combined with lysophosphatidylcholine (LPC) as a substrate, PF-8380's efficacy remained intact. When human whole blood was treated with PF-8380 for two hours at an IC50 of 101 nM, autocrine motility factors were suppressed [1]. Lysophospholipase D (lysoPLD) activity is exhibited by the enzyme autotaxin (ATX), which catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). After applying 1 μM PF-8380 as a pretreatment to GL261 and U87-MG cells, they were exposed to 4 Gy of radiation, which led to a decrease in clone survival, reduced migration (33% in GL261; P=0.002 and 17.9% in U87-MG; P=0.012), decreased invasion (35.6% in GL261; P=0.0037; 31.8% in U87-MG; P=0.002), and attenuate radiation-induced Akt phosphorylation [2].
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| ln Vivo |
PF-8380's pharmacokinetic properties were assessed over the course of 24 hours at intravenous dosages of 1 mg/kg and oral doses ranging from 1 to 100 mg/kg. PF-8380 has an effective t1/2 of 1.2 hours, a steady-state distribution volume of 3.2 L/kg, and an average clearance rate of 31 mL/min/kg. There is moderate oral bioavailability, with a range of 43% to 83%. As single oral dosages are increased, plasma concentrations rise as well; however, the rate of increase in Cmax is less than proportional to doses of 10 to 100 mg/kg but about proportionate to doses of 1 to 10 mg/kg. Up to 100 mg/kg, exposure to PF-8380 is roughly dose-proportional and linear, as indicated by the area under the curve. The amounts of plasma C16:0, C18:0, and C20:0 LPA were tested right away following collection. With the 3 mg/kg dose, the largest drop in LPA levels was seen at 0.5 hours, and within 24 hours, all LPAs were returned to or exceeded baseline [1]. Tumor-associated vascularity increased by a moderate 20% after treatment with 10 mg/kg PF-8380 (P=0.497). 45 minutes prior to 4 Gy irradiation, PF-8380 treatment decreased vascularity in mice treated relative to controls by approximately 48% (P=0.031) and by 65% (P=0.011) in mice treated with radiation alone[2].
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| 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 |
| Molecular Formula |
C22H21CL2N3O5
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|---|---|
| Molecular Weight |
478.3252
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| CAS # |
1144035-53-9
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| Related CAS # |
PF-8380 hydrochloride;2070015-01-7
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| SMILES |
O=C(N1CCN(CCC(C2=CC=C3NC(OC3=C2)=O)=O)CC1)OCC4=CC(Cl)=CC(Cl)=C4
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| Chemical Name |
3,5-dichlorobenzyl 4-(3-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propyl)piperazine-1-carboxylate
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| Synonyms |
PF-8380; PF 8380; PF8380;
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~209.06 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.67 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.67 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.67 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10 mg/mL (20.91 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 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 | |
| 10 mM | 0.2091 mL | 1.0453 mL | 2.0906 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Inhibition of ATX reduces Akt Phosphorylation in GBM cells grown in co-culture.Front Oncol.2013 Sep 17;3:236. |
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 Inhibition of ATX abrogates radiation induced tumor neovascularization.Front Oncol.2013 Sep 17;3:236. |
 Inhibition of ATX in combination with irradiation delays tumor growth in a heterotopic tumor model of GL261.Front Oncol.2013 Sep 17;3:236. |
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