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Purity: ≥98%
PF-8380 HCl 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 |
The pharmacokinetic properties of PF-8380 were examined over 24 hours at dosages of 1 mg/kg intravenously and oral doses of 1 to 100 mg/kg. The average clearance rate of PF-8380 is 31 mL/min/kg, the steady-state distribution volume is 3.2 L/kg, and the effective t1/2 is 1.2 h. Oral bioavailability is moderate, ranging from 43% to 83%. Plasma concentrations increase with increasing single oral doses, however the rate of increase in Cmax is approximately proportionate to doses of 1 to 10 mg/kg but less than proportional to doses of 10 to 100 mg/kg. Exposure to PF-8380, measured by the area under the curve, is generally dose-proportional and linear up to 100 mg/kg. Plasma C16:0, C18:0 and C20:0 LPA levels were tested immediately after collection. The highest reduction in LPA levels was found at 0.5 hours with the 3 mg/kg dosage, with all LPAs recovering to or above baseline by 24 hours [1]. Treatment with 10 mg/kg PF-8380 resulted in a modest 20% increase in tumor-associated vascularity (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 |
| CAS # |
2070015-01-7
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| Related CAS # |
PF-8380;1144035-53-9
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| SMILES |
O=C(N1CCN(CC1)CCC(C2=CC(O3)=C(C=C2)NC3=O)=O)OCC4=CC(Cl)=CC(Cl)=C4.[H]Cl
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| InChi Key |
JMSUDQYHPSNBSN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H21Cl2N3O5/c23-16-9-14(10-17(24)12-16)13-31-22(30)27-7-5-26(6-8-27)4-3-19(28)15-1-2-18-20(11-15)32-21(29)25-18/h1-2,9-12H,3-8,13H2,(H,25,29)
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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 hydrochloride
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| Synonyms |
PF8380 HCl; PF-8380; PF 8380
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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 : ≥ 5.2 mg/mL (~10.10 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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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