Picropodophyllin
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Hodoodo CAT#: H205812

CAS#: 477-47-4

Description: Picropodophyllin, also known as Picropodophyllotoxin, AXL1717 or PPP, 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.


Chemical Structure

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Picropodophyllin
CAS# 477-47-4

Theoretical Analysis

Hodoodo Cat#: H205812
Name: Picropodophyllin
CAS#: 477-47-4
Chemical Formula: C22H22O8
Exact Mass: 414.13
Molecular Weight: 414.410
Elemental Analysis: C, 63.76; H, 5.35; O, 30.89

Price and Availability

Size Price Availability Quantity
10mg USD 110 Ready to ship
25mg USD 225 Ready to ship
50mg USD 385 Ready to ship
100mg USD 685 Ready to ship
200mg USD 1250 Ready to ship
500mg USD 1950 Ready to ship
1g USD 2950 Ready to ship
2g USD 5250 Ready to ship
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Synonym: AXL1717; AXL-1717; AXL 1717; PPP; picropodophyllin; Picropodophyllotoxin.

IUPAC/Chemical Name: (5R,5aS,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,5a,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one

InChi Key: YJGVMLPVUAXIQN-HAEOHBJNSA-N

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

SMILES Code: O=C1OC[C@]2([H])[C@@H](O)C3=C(C=C4OCOC4=C3)[C@@H](C5=CC(OC)=C(OC)C(OC)=C5)[C@@]21[H]

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info: AXL1717 is the first targeted oral small-molecule IGF-1 receptor inhibitor with no effect on the insulin receptor. AXL1717 is presently undergoing phase I/II clinical trials and the compound combines a superior preclinical efficacy against numerous tumors with an excellent tolerability profile. Most tumor cells are dependent on the IGF-1 receptor signal pathway and the IGF-1 receptor is therefore regarded as a very promising target for cancer therapy. To date, there are no IGF-1 receptor inhibitor drugs on the market.   AXL1717 is currently being developed by Axelar (source: http://www.axelar.se/pipeline.html).   AXL1717 demonstrates strong anti-tumor efficacy, including tumor extermination, in animals xenografted with human malignant cells, including breast cancer, prostate cancer, glioblastoma (intracerebral implants), malignant melanoma, sarcoma and multiple myeloma. Axelar has successfully completed its first Phase I/II clinical study in 49 advanced-stage cancer patients with solid tumors. The study reached all objectives with respect to safety, bioavailability and the recommended phase II dose was identified. Even though the study was not primarily designed for efficacy assessments, signs suggesting treatment benefit were reported.          

Biological target: Picropodophyllin (AXL1717) is a selective insulin-like growth factor-1 receptor (IGF-1R) inhibitor with an IC50 of 1 nM.
In vitro activity: PPP was previously reported to induce apoptosis and CDK1 is known to regulate apoptosis. In the present study PPP induced 2.5 to 3fold increase in apoptosis compared to controls (statistically significant only in HepG2 and MCF-7 cells) (Fig. S3A, B) with reduced levels of Mcl-1 (Fig. S3C, D). In addition, PARP cleavage was observed in MCF-7 cells after 48 h of PPP treatment (Fig. S3D). To investigate whether these alterations were due to CDK1 activity, CDK1 was depleted using specific siRNA in MCF-7 cells. Depletion of CDK1 (by 80-90 %) resulted in reduced Mcl-1 levels and PARP and Caspase3 cleavage, regardless of PPP treatment (Fig. S3D). n PPP-treated HepG2 cells the percentage of pH3-positive cells increased after PPP addition to 4- and 3-fold at 8 and 24h, respectively. Similar effects were observed in Hep3B and A549 cells (Fig.4A).. The potential effect of IGF-1R on the mitotic arrest was assessed in a knock-down experiment in Hep3B cells using siRNA, showing that IGF-1R depletion did not affect the PPP-induced accumulation of cells in mitosis (Fig 4B). In conclusion, the results demonstrate a novel mechanism of action of the anticancer agent PPP, interfering with microtubule dynamics and leading to mitotic arrest Reference: Oncotarget. 2014 Sep; 5(18): 8379–8392. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226690/
In vivo activity: Finally, a mouse xenotransplantation model was employed. In the experiment intramuscular injections of RH30 (ARMS) cells to SCID-beige mice were performed and further divided them into two groups (control and PPP treated). A total of 10 SCID/beige mice were injected with RH30 cells (intramuscular, 6 × 106 cells per leg). After two weeks from inoculation intraperitoneal injection of PPP (40 mg/kg/24 h) and vehicle alone (50 μl DMSO) was started. It was noted, that PPP-injected mice grew significantly smaller tumours as compared to controls (Fig.7a). What is more is that bone marrow, lungs and liver were collected in order to estimate RMS cells seeding efficiency to these organs. DNA was isolated and using real-time RT-PCR, human α-satellite sequences and murine βactin were isolated. It was found that mouse bearing RMS tumours that were treated with PPP exhibited 4 times lower amount of human cancer cells infiltrating bone marrow controls (Fig.7b). Seeding efficiency to lungs and liver was not affected by PPP treatment. What is also very important, there was no notice of significant side effects of PPP treatment, however mice injected with PPP had lower body mass (Additional file 1). Reference: BMC Cancer. 2017; 17: 532. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550998/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 15.0 36.20

Preparing Stock Solutions

The following data is based on the product molecular weight 414.41 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Tarnowski M, Tkacz M, Zgutka K, Bujak J, Kopytko P, Pawlik A. Picropodophyllin (PPP) is a potent rhabdomyosarcoma growth inhibitor both in vitro and in vivo. BMC Cancer. 2017 Aug 9;17(1):532. doi: 10.1186/s12885-017-3495-y. PMID: 28793874; PMCID: PMC5550998. 2. Waraky A, Akopyan K, Parrow V, Strömberg T, Axelson M, Abrahmsén L, Lindqvist A, Larsson O, Aleem E. Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via insulin-like growth factor-1 receptor-independent mechanism. Oncotarget. 2014 Sep 30;5(18):8379-92. doi: 10.18632/oncotarget.2292. PMID: 25268741; PMCID: PMC4226690. 3. Economou MA, Andersson S, Vasilcanu D, All-Ericsson C, Menu E, Girnita A, Girnita L, Axelson M, Seregard S, Larsson O. Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma. Acta Ophthalmol. 2008 Nov;86 Thesis 4:35-41. doi: 10.1111/j.1755-3768.2008.01184.x. PMID: 19032680.
In vitro protocol: 1. Tarnowski M, Tkacz M, Zgutka K, Bujak J, Kopytko P, Pawlik A. Picropodophyllin (PPP) is a potent rhabdomyosarcoma growth inhibitor both in vitro and in vivo. BMC Cancer. 2017 Aug 9;17(1):532. doi: 10.1186/s12885-017-3495-y. PMID: 28793874; PMCID: PMC5550998. 2. Waraky A, Akopyan K, Parrow V, Strömberg T, Axelson M, Abrahmsén L, Lindqvist A, Larsson O, Aleem E. Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via insulin-like growth factor-1 receptor-independent mechanism. Oncotarget. 2014 Sep 30;5(18):8379-92. doi: 10.18632/oncotarget.2292. PMID: 25268741; PMCID: PMC4226690.
In vivo protocol: 1. Economou MA, Andersson S, Vasilcanu D, All-Ericsson C, Menu E, Girnita A, Girnita L, Axelson M, Seregard S, Larsson O. Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma. Acta Ophthalmol. 2008 Nov;86 Thesis 4:35-41. doi: 10.1111/j.1755-3768.2008.01184.x. PMID: 19032680. 2. Tarnowski M, Tkacz M, Zgutka K, Bujak J, Kopytko P, Pawlik A. Picropodophyllin (PPP) is a potent rhabdomyosarcoma growth inhibitor both in vitro and in vivo. BMC Cancer. 2017 Aug 9;17(1):532. doi: 10.1186/s12885-017-3495-y. PMID: 28793874; PMCID: PMC5550998.

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1: E C, Li J, Shao D, Zhang D, Pan Y, Chen L, Zhang X. The insulin-like growth factor-I receptor inhibitor picropodophyllin-induced selective apoptosis of hepatocellular carcinoma cell through a caspase-dependent mitochondrial pathway. Oncol Res. 2014;21(2):103-10. doi: 10.3727/096504013X13808175127324. PubMed PMID: 24406046.

2: Huang Z, Fang Z, Zhen H, Zhou L, Amin HM, Shi P. Inhibition of type I insulin-like growth factor receptor tyrosine kinase by picropodophyllin induces apoptosis and cell cycle arrest in T lymphoblastic leukemia/lymphoma. Leuk Lymphoma. 2014 Feb 17. [Epub ahead of print] PubMed PMID: 24206093.

3: Wang Q, Wei F, Lv G, Li C, Liu T, Hadjipanayis CG, Zhang G, Hao C, Bellail AC. The association of TP53 mutations with the resistance of colorectal carcinoma to the insulin-like growth factor-1 receptor inhibitor picropodophyllin. BMC Cancer. 2013 Nov 4;13:521. doi: 10.1186/1471-2407-13-521. PubMed PMID: 24182354; PubMed Central PMCID: PMC3840673.

4: Yin SC, Guo W, Tao ZZ. Picropodophyllin inhibits tumor growth of human nasopharyngeal carcinoma in a mouse model. Biochem Biophys Res Commun. 2013 Sep 13;439(1):1-5. doi: 10.1016/j.bbrc.2013.08.050. Epub 2013 Aug 22. PubMed PMID: 23973483.

5: Wu X, Sooman L, Wickström M, Fryknäs M, Dyrager C, Lennartsson J, Gullbo J. Alternative cytotoxic effects of the postulated IGF-IR inhibitor picropodophyllin in vitro. Mol Cancer Ther. 2013 Aug;12(8):1526-36. doi: 10.1158/1535-7163.MCT-13-0091. Epub 2013 May 22. PubMed PMID: 23699657.

6: Lu X, Wang L, Mei J, Wang X, Zhu X, Zhang Q, Lv J. Picropodophyllin inhibits epithelial ovarian cancer cells in vitro and in vivo. Biochem Biophys Res Commun. 2013 Jun 7;435(3):385-90. doi: 10.1016/j.bbrc.2013.04.097. Epub 2013 May 9. PubMed PMID: 23665331.

7: Lemaire M, Fristedt C, Agarwal P, Menu E, Van Valckenborgh E, De Bruyne E, Österborg A, Atadja P, Larsson O, Axelson M, Van Camp B, Jernberg-Wiklund H, Vanderkerken K. The HDAC inhibitor LBH589 enhances the antimyeloma effects of the IGF-1RTK inhibitor picropodophyllin. Clin Cancer Res. 2012 Apr 15;18(8):2230-9. doi: 10.1158/1078-0432.CCR-11-1764. Epub 2012 Mar 5. PubMed PMID: 22392915.

8: Feng X, Aleem E, Lin Y, Axelson M, Larsson O, Strömberg T. Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: clinical implications. Int J Oncol. 2012 Apr;40(4):1251-8. doi: 10.3892/ijo.2011.1281. Epub 2011 Dec 6. PubMed PMID: 22159423; PubMed Central PMCID: PMC3584617.

9: Doghman M, Axelson M, Lalli E. Potent inhibitory effect of the cyclolignan picropodophyllin (PPP) on human adrenocortical carcinoma cells proliferation. Am J Cancer Res. 2011;1(3):356-361. Epub 2011 Jan 5. PubMed PMID: 21968616; PubMed Central PMCID: PMC3180063.

10: Hashemi J, Worrall C, Vasilcanu D, Fryknäs M, Sulaiman L, Karimi M, Weng WH, Lui WO, Rudduck C, Axelson M, Jernberg-Wiklund H, Girnita L, Larsson O, Larsson C. Molecular characterization of acquired tolerance of tumor cells to picropodophyllin (PPP). PLoS One. 2011 Mar 14;6(3):e14757. doi: 10.1371/journal.pone.0014757. PubMed PMID: 21423728; PubMed Central PMCID: PMC3056661.

11: Rönquist-Nii Y, Eksborg S, Axelson M, Harmenberg J, Ekman S, Bergqvist M, Beck O. Determination of picropodophyllin and its isomer podophyllotoxin in human serum samples with electrospray ionization of hexylamine adducts by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Feb 15;879(5-6):326-34. doi: 10.1016/j.jchromb.2010.12.017. Epub 2010 Dec 28. Erratum in: J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Mar 15;889-890:148. Ekman, Simon [added]; Bergqvist, Michael [added]. PubMed PMID: 21251888.

12: Ohshima-Hosoyama S, Hosoyama T, Nelon LD, Keller C. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma. Biochem Biophys Res Commun. 2010 Sep 3;399(4):727-32. doi: 10.1016/j.bbrc.2010.08.009. Epub 2010 Aug 6. PubMed PMID: 20692232.

13: Yin S, Girnita A, Strömberg T, Khan Z, Andersson S, Zheng H, Ericsson C, Axelson M, Nistér M, Larsson O, Ekström TJ, Girnita L. Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neuro Oncol. 2010 Jan;12(1):19-27. doi: 10.1093/neuonc/nop008. Epub 2009 Oct 20. PubMed PMID: 20150364; PubMed Central PMCID: PMC2940558.

14: Duan Z, Choy E, Harmon D, Yang C, Ryu K, Schwab J, Mankin H, Hornicek FJ. Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines. Mol Cancer Ther. 2009 Aug;8(8):2122-30. doi: 10.1158/1535-7163.MCT-09-0115. Epub 2009 Jul 28. PubMed PMID: 19638450; PubMed Central PMCID: PMC2766237.

15: Economou MA, Wu J, Vasilcanu D, Rosengren L, All-Ericsson C, van der Ploeg I, Menu E, Girnita L, Axelson M, Larsson O, Seregard S, Kvanta A. Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor. Acta Ophthalmol. 2008 Nov;86 Thesis 4:42-9. doi: 10.1111/j.1755-3768.2008.01185.x. PubMed PMID: 19032681.

16: Economou MA, Andersson S, Vasilcanu D, All-Ericsson C, Menu E, Girnita A, Girnita L, Axelson M, Seregard S, Larsson O. Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma. Acta Ophthalmol. 2008 Nov;86 Thesis 4:35-41. doi: 10.1111/j.1755-3768.2008.01184.x. PubMed PMID: 19032680.

17: Girnita A, All-Ericsson C, Economou MA, Aström K, Axelson M, Seregard S, Larsson O, Girnita L. The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Acta Ophthalmol. 2008 Nov;86 Thesis 4:26-34. doi: 10.1111/j.1755-3768.2008.01183.x. PubMed PMID: 19032679.

18: Tomizawa M, Yokosuka O. Picropodophyllin suppresses the proliferation and invasion of hepatocellular carcinoma under serum starvation. Mol Med Rep. 2008 Sep-Oct;1(5):685-8. doi: 10.3892/mmr_00000013. PubMed PMID: 21479470.

19: Vitale M, Prestat G, Lopes D, Madec D, Kammerer C, Poli G, Girnita L. New picropodophyllin analogs via palladium-catalyzed allylic alkylation-Hiyama cross-coupling sequences. J Org Chem. 2008 Aug 1;73(15):5795-805. doi: 10.1021/jo800707q. Epub 2008 Jun 25. PubMed PMID: 18576606.

20: Economou MA, Wu J, Vasilcanu D, Rosengren L, All-Ericsson C, van der Ploeg I, Menu E, Girnita L, Axelson M, Larsson O, Seregard S, Kvanta A. Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor. Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2620-6. doi: 10.1167/iovs.07-0742. PubMed PMID: 18515591.