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Purity: ≥98%
Picropodophyllin (also known as Picropodophyllotoxin, AXL1717 or PPP), a naturally occuring cyclolignan alkaloid isolated from the mayapple plant family, is a novel, potent, orally bioavailable and selective small molecule inhibitor of the IGF-1R with potential antineoplastic activity. In SCID mice xenografted with human ES-1, BE, and PC3, it exhibits strong in vivo antitumor efficacy.
| Targets |
IGF-1R (IC50 = 1 nM)
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|---|---|
| ln Vitro |
PPP effectively inhibits the phosphorylation of Erk1/2, Akt (Ser 473), and IGF-1-stimulated IGF-1R in intact cells. Picropodophyllin specifically suppresses growth and causes IGF-1R-positive tumor cells grown in culture to undergo apoptosis.[1] By further reducing cell viability and increasing apoptosis, picropodophyllin synergistically sensitizes HMCL, primary human MM, and murine 5T33MM cells to ABT-737 and ABT-199.[3] Sorafenib and picropodialdoxolin both work in concert to inhibit the growth and motility of hepatocellular carcinoma cells.[4]
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| ln Vivo |
Picropodophyllin (20 mg/kg/12 h, i.p.) completely suppresses tumor growth in SCID mice xenografted with human ES-1, BE, and PC3.[1] Picropodophyllin also significantly increases survival in the 5T33MM mouse model and exhibits strong antitumor activity.[2]
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| Enzyme Assay |
The phosphorylation of pTG by IGF-1R-catalyzed substrate is assayed using a 96-well plate tyrosine kinase assay kit. To represent "non-IGF-1R tyrosine kinases," we use recombinant epidermal growth factor receptor, immunoprecipitated IR from HEPG2, immunoprecipitated IGF-1R from P6 cells, and IGF-1R immunodepleted supernatant from P6. The kinase reaction is triggered by the addition of ATP after the receptors have been treated for 30 minutes with the desired compounds in the kinase buffer (20 mM HEPES buffer (pH 7.4), 0.1 MnCl2, 0.2 Na3VO4, and 20 mM MgCl2). A phosphotyrosine-specific monoclonal antibody conjugated to horseradish peroxidase, clone PT-66, is used to probe the phosphorylated polymer substrate. O-phenylenediamine dihydrochloride, a chromogenic substrate for horseradish peroxidase, is used to develop color, and spectrophotometry (an ELISA reader) enables quantification. An ELISA sandwich test is used to measure IGF-1R tyrosine autophosphorylation. IGF-1R β-subunit antibody (1 μg/well) is coated onto 96-well plates and allowed to sit overnight at 4°C. 80 μg/well of the P6 cell line's total protein lysate is added after the plates are blocked for one hour with 1% BSA in PBS Tween. Total R-cell line protein lysate is used as a negative control. Before kinase activation with ATP, the evaluated compounds are added to tyrosine kinase buffer at room temperature and allowed to sit for 30 minutes. Use the Sigma kit (see above) to perform the kinase assay.
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| Cell Assay |
The results are made using the Cell Proliferation Kit II, which is based on the respiratory chain of viable cells performing a colorimetric change of the yellow tetrazolium salt 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt in orange formazan dye. Every experiment and standard is run through three times.
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| Animal Protocol |
In a sterile setting, plastic isolators are used to house four to five-week-old pathogen-free SCID mice. In a 0.2 mL volume of sterile saline solution, ES-1, BE, and PC3 cells (all of which have been shown to express IGF-1R), or R-v-src (IGF-1R negative) and P12 (overexpressing IGF-1 and IGF-1R), are injected subcutaneously at a density of 107 cells/mice. 107JC murine breast cancer cells per mouse are injected into immunocompetent Balb-c mice in a 0.15 mL volume of sterile saline solution. Picropodophyllin (AXL1717) (20 mg/kg/12 h) is administered intraperitoneally (i.p.) once a day in a volume of 10 μL of DMSO: vegetable oil (10:1 (v/v)). Only the vehicle is used to treat the control mice. Each group receives treatment for three animals. Using vernier calipers, tumor growth is measured every other day, and tumor volumes are computed. The mice are sacrificed at the conclusion of the experiments so that the lesions can be histologically analyzed, and they are closely monitored for the occurrence of any adverse effects. A different experiment that involved systemically and locally treating tumor-free mice with Picropodophyllin (AXL1717) and analyzing the organ histology supports earlier findings that the drug seems to be nontoxic.
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| References |
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| Additional Infomation |
Picropodophyllotoxin is an organic heterotetracyclic compound that has a furonaphthodioxole skeleton bearing 3,4,5-trimethoxyphenyl and hydroxy substituents. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor, an insulin-like growth factor receptor 1 antagonist and a plant metabolite. It is a lignan, a furonaphthodioxole and an organic heterotetracyclic compound.
Picropodophyllin has been investigated for the treatment of Non Small Cell Lung Cancer. Picropodophyllin has been reported in Juniperus sabina, Juniperus thurifera, and other organisms with data available. Picropodophyllin is a cyclolignan alkaloid found in the mayapple plant family (Podophyllum peltatum), and a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF1R) with potential antineoplastic activity. Picropodophyllin specifically inhibits the activity and downregulates the cellular expression of IGF1R without interfering with activities of other growth factor receptors, such as receptors for insulin, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor and mast/stem cell growth factor (KIT). This agent shows potent activity in the suppression o f tumor cell proliferation and the induction of tumor cell apoptosis. IGF1R, a receptor tyrosine kinase overexpressed in a variety of human cancers, plays a critical role in the growth and survival of many types of cancer cells. |
| Molecular Formula |
C22H22O8
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|---|---|
| Molecular Weight |
414.41
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| Exact Mass |
414.131
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| Elemental Analysis |
C, 63.76; H, 5.35; O, 30.89
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| CAS # |
477-47-4
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| Related CAS # |
Picropodophyllin-d6
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| PubChem CID |
72435
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| Appearance |
white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
597.9±50.0 °C at 760 mmHg
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| Melting Point |
225-227ºC
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| Flash Point |
210.2±23.6 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.606
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| LogP |
1.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
629
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| Defined Atom Stereocenter Count |
4
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| SMILES |
O1C([C@@]2([H])[C@]([H])(C3C([H])=C(C(=C(C=3[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])C3=C([H])C4=C(C([H])=C3[C@@]([H])([C@@]2([H])C1([H])[H])O[H])OC([H])([H])O4)=O
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| InChi Key |
YJGVMLPVUAXIQN-HAEOHBJNSA-N
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| InChi Code |
InChI=1S/C22H22O8/c1-25-16-4-10(5-17(26-2)21(16)27-3)18-11-6-14-15(30-9-29-14)7-12(11)20(23)13-8-28-22(24)19(13)18/h4-7,13,18-20,23H,8-9H2,1-3H3/t13-,18+,19+,20-/m0/s1
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| Chemical Name |
(5R,5aR,8aS,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
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| Synonyms |
Picropodophyllotoxin, AXL1717; PPP; AXL-1717; AXL 1717; PPP; picropodophyllin
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| HS Tariff Code |
2934.99.9001
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 2 mg/mL (4.83 mM) in 15% Cremophor EL + 85% 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. View More
Solubility in Formulation 3: 1% CMC Na: 30 mg/mL Solubility in Formulation 4: 3 mg/mL (7.24 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication (<60°C). 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 | 2.4131 mL | 12.0653 mL | 24.1307 mL | |
| 5 mM | 0.4826 mL | 2.4131 mL | 4.8261 mL | |
| 10 mM | 0.2413 mL | 1.2065 mL | 2.4131 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01466647 | Completed | Drug: AXL1717 | Non Small Cell Lung Cancer | Axelar AB | January 2011 | Phase 1 |
| NCT01561456 | Completed | Drug: AXL1717 Drug: Docetaxel |
Non-small-cell Lung Cancer Squamous Cell Carcinoma |
Axelar AB | December 2011 | Phase 2 |
| NCT01725555 | Completed | Drug: Fasted treatment: AXL1717 Drug: Fed treatment: AXL1717 |
Hematological Malignancies Solid Tumors |
Axelar AB | October 2012 | Phase 1 |
| NCT01062620 | Completed | Drug: AXL1717 | Solid Tumors | Axelar AB | April 2008 | Phase 1 |
| NCT01721577 | Terminated | Drug: AXL1717 | Glioblastoma Gliosarcoma |
Rush University Medical Center | December 2012 | Phase 1 Phase 2 |
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