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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)
Insulin-like Growth Factor 1 Receptor (IGF-1R) (IC50 = 8.5 nM for recombinant human IGF-1R kinase); no activity against IR, EGFR, HER2 (IC50 > 1000 nM) [1] - Confirmed IGF-1R as primary target (multiple myeloma model; no additional IC50 values) [2][5] - Confirmed IGF-1R targeting (hepatocellular carcinoma model; consistent with [1]’s IC50) [4] |
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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]
Inhibited solid tumor cell proliferation: Breast cancer MCF-7 (IC50 = 19.2 nM), lung cancer H460 (IC50 = 22.6 nM); 100 nM Picropodophyllin reduced MCF-7 colony formation by 75% (14-day culture) [1] - Suppressed multiple myeloma (MM) cell growth: 5T33MM.1 (IC50 = 15.8 nM), RPMI-8226 (IC50 = 18.3 nM); 50 nM Picropodophyllin decreased p-IGF-1R (Tyr1135/1136) by 90% in 5T33MM.1 cells (2 hours) [2][5] - Induced MM cell apoptosis: 200 nM Picropodophyllin increased Annexin V-positive RPMI-8226 cells from 7% to 45% (48 hours); G2/M phase accumulation (from 18% to 42%, flow cytometry) [5] - Synergized with BH3-mimetic (ABT-737) in MM: 100 nM Picropodophyllin + 50 nM ABT-737 reduced viability by 82% (vs. 45%/38% for monotherapy); synergistic index = 0.56 [3] - Synergized with sorafenib in(HCC): 150 nM Picropodophyllin + 200 nM sorafenib reduced HepG2 viability by 78% (vs. 42%/35% for monotherapy); inhibited migration by 68% [4] |
| 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]
In 5T33MM multiple myeloma mice (C57BL/KaLwRij): Intraperitoneal Picropodophyllin (10 mg/kg, twice daily) for 21 days reduced tumor burden by 72%; median survival extended from 35 days (vehicle) to 62 days [2] - In nude mice bearing RPMI-8226 xenografts: Oral Picropodophyllin (15 mg/kg/day) for 28 days achieved 76% tumor growth inhibition (TGI); tumor p-IGF-1R reduced by 78% [5] - In nude mice bearing HepG2 HCC xenografts: Picropodophyllin (12 mg/kg/day, oral) + sorafenib (30 mg/kg/day, oral) for 35 days reduced tumor volume by 83% (vs. 45%/40% for monotherapy) [4] |
| 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.
IGF-1R kinase activity assay (literature 1): Recombinant human IGF-1R kinase domain (50 ng/well) was incubated with Picropodophyllin (0.1-100 nM) in buffer (25 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT) at 37°C for 20 minutes. 10 μM ATP and fluorescent peptide substrate were added, followed by 60-minute incubation at 30°C. Activity was measured via HTRF (excitation 340 nm, emission 665 nm); IC50 calculated via nonlinear regression [1] |
| 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.
Solid tumor proliferation assay (MCF-7/H460, [1]): Cells were seeded in 96-well plates (5×10³ cells/well) and treated with Picropodophyllin (0.1 nM-1 μM) for 72 hours. Viability was measured via MTT assay; absorbance at 570 nm recorded; IC50 determined via four-parameter fitting [1] - MM Western blot assay (5T33MM.1, [2]): Cells were treated with Picropodophyllin (10-200 nM) for 2 hours, lysed in RIPA buffer (with protease inhibitors). 30 μg protein was separated by 8% SDS-PAGE, probed with p-IGF-1R, p-AKT, p-ERK antibodies; signals detected via chemiluminescence [2] - MM apoptosis assay (RPMI-8226, [5]): Cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with Picropodophyllin (50-200 nM) for 48 hours. Stained with Annexin V-FITC/PI, analyzed by flow cytometry; cell cycle phase distribution measured via propidium iodide staining [5] - HCC combination assay (HepG2, [4]): Cells were treated with Picropodophyllin (10-300 nM) + sorafenib (50-500 nM) for 96 hours. Viability measured via colorimetric assay; synergistic index calculated by Chou-Talalay method [4] |
| 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 10 7 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.
5T33MM multiple myeloma model (C57BL/KaLwRij mice, [2]): 8-week-old female mice were inoculated with 5×10⁶ 5T33MM cells via intravenous injection. Seven days later, mice received Picropodophyllin (10 mg/kg, intraperitoneal injection) twice daily for 21 days. Drug dissolved in 10% DMSO + 40% PEG400 + 50% saline; tumor burden measured via serum paraprotein levels [2] - RPMI-8226 xenograft model (nude mice, [5]): Female nude mice were subcutaneously injected with 2×10⁶ RPMI-8226 cells. When tumors reached 100 mm³, mice received Picropodophyllin (15 mg/kg/day, oral gavage) for 28 days. Drug dissolved in 0.5% methylcellulose; tumor volume measured every 3 days [5] - HepG2 HCC xenograft model (nude mice, [4]): Mice were implanted with 1×10⁷ HepG2 cells subcutaneously. Tumors reaching 120 mm³ received Picropodophyllin (12 mg/kg/day, oral) + sorafenib (30 mg/kg/day, oral) for 35 days. Both drugs dissolved in 0.5% methylcellulose; survival time recorded [4] |
| ADME/Pharmacokinetics |
In mice (Reference 2): Intraperitoneal injection (10 mg/kg) of Picropodophyllin resulted in a plasma half-life (t1/2) of 3.8 hours and a clearance rate of 16 mL/min/kg [2]. In mice (Reference 5): Oral bioavailability was 35% (15 mg/kg dose); peak plasma concentration (Cmax) was 3.2 μM 1.8 hours after oral administration [5]. Plasma protein binding was 99.0% (human plasma, ultrafiltration) [1].
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| Toxicity/Toxicokinetics |
In the 21-day 5T33MM study ([2]): no significant weight loss (>8%) was observed; serum ALT = 27 ± 4 U/L, BUN = 18 ± 3 mg/dL (both within the normal range); no histopathological changes were observed in the liver/kidneys [2]
- In the 28-day RPMI-8226 study ([5]): 1 out of 8 mice experienced mild diarrhea (resolved on day 7); no organ toxicity was observed [5] - In the 35-day HCC combination therapy study ([4]): no treatment-related deaths were observed; serum AST = 51 ± 6 U/L (normal) [4] |
| References |
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| Additional Infomation |
Picropodophyllotoxin is an organic heterotetracyclic compound with a furanonaphthalenedioxane heterocyclic skeleton and 3,4,5-trimethoxyphenyl and hydroxyl substituents. It possesses antitumor activity and can be used as a tyrosine kinase inhibitor, insulin-like growth factor receptor 1 antagonist, and plant metabolite. It is a lignan, furanonaphthalenedioxane heterocyclic compound, and organic heterotetracyclic compound. Matrine has been investigated for the treatment of non-small cell lung cancer. It has been reported to exist in Juniper (Juniperus sabina), Juniper (Juniperus thurifera), and other organisms with relevant data. Matrine is a cyclic lignan alkaloid found in Podophyllum peltatum and is a small molecule inhibitor of insulin-like growth factor 1 receptor (IGF1R) with potential antitumor activity. Matrine specifically inhibits the activity of IGF1R and downregulates its cellular expression without interfering with the activity of other growth factor receptors, such as insulin receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, and mast cell/stem cell growth factor receptor (KIT). This drug exhibits significant activity in inhibiting tumor cell proliferation and inducing tumor cell apoptosis. IGF1R is a receptor tyrosine kinase that is overexpressed in various human cancers and plays a crucial role in the growth and survival of various cancer cells.
Picropodophyllin (PPP) is a cyclolignan-derived selective IGF-1R tyrosine kinase inhibitor initially developed for the treatment of IGF-1R-dependent cancers (multiple myeloma, breast cancer, lung cancer, liver cancer)[1][2][4][5] - Its antitumor mechanisms include inhibiting IGF-1R autophosphorylation, blocking the PI3K-AKT/MEK-ERK pathway, inducing G2/M phase cell cycle arrest, and promoting apoptosis[1][5] - It synergizes with BH3 mimics (e.g., ABT-737) in multiple myeloma and with sorafenib in liver cancer by targeting complementary signaling pathways[3][4] |
| 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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