AXL1717 | Picropdophyllin | Picropodophyllotoxin | CAS#477-47-4 | IGF1R inhibitor

MedKoo Cat#: 205812 | Name: Picropodophyllin

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

Picropodophyllin

CAS#477-47-4

Theoretical Analysis

MedKoo Cat#: 205812

Name: Picropodophyllin

CAS#: 477-47-4

Chemical Formula: C22H22O8

Exact Mass: 414.1315

Molecular Weight: 414.41

Elemental Analysis: C, 63.76; H, 5.35; O, 30.89

Price and Availability

Size	Price	Availability
10mg	USD 110.00	Ready to ship
25mg	USD 225.00	Ready to ship
50mg	USD 385.00	Ready to ship
100mg	USD 685.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 1,950.00	Ready to ship
1g	USD 2,950.00	Ready to ship
2g	USD 5,250.00	Ready to ship

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Related CAS #

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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.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#TZC50713

QC Data

View QC data: current batch, Lot#TZC50713

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	15.0	36.20

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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:

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.

1: Yang J, Qin S, Sun N, Cai Y, Li J, Zhai Z, An J, Wang H, Du R, Qin J. Neohesperidin alleviates the inhibitory effect of bisphenol A on the myogenic differentiation of umbilical cord mesenchymal stem cells via the IGF1R/AKT1/RHOA signaling pathway. Ecotoxicol Environ Saf. 2024 Jul 30;283:116804. doi: 10.1016/j.ecoenv.2024.116804. Epub ahead of print. PMID: 39083871. 2: Hou L, Ma J, Feng X, Chen J, Dong BH, Xiao L, Zhang X, Guo B. Caffeic acid and diabetic neuropathy: Investigating protective effects and insulin-like growth factor 1 (IGF-1)-related antioxidative and anti-inflammatory mechanisms in mice. Heliyon. 2024 Jun 6;10(12):e32623. doi: 10.1016/j.heliyon.2024.e32623. PMID: 38975173; PMCID: PMC11225750. 3: Mao D, Wang K, Jiang H, Mi J, Pan X, Zhao G, Rui Y. Suppression of Overactive Insulin-Like Growth Factor 1 Attenuates Trauma-Induced Heterotopic Ossification in Mice. Am J Pathol. 2024 Mar;194(3):430-446. doi: 10.1016/j.ajpath.2023.11.012. Epub 2023 Dec 13. PMID: 38101566. 4: Li X, Wang G, Zhou X, Zhao H, Chen X, Cui Q, Li M, Gao X, Wei X, Ye L, Li D, Hong P. Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT. Phytother Res. 2023 Oct;37(10):4740-4754. doi: 10.1002/ptr.7943. Epub 2023 Aug 9. PMID: 37559472. 5: Nwachukwu CU, Robinson RS, Woad KJ. Effect of insulin-like growth factor system on luteinising angiogenesis. Reprod Fertil. 2023 Mar 1;4(2):e220057. doi: 10.1530/RAF-22-0057. Epub ahead of print. PMID: 37052337; PMCID: PMC10160534. 6: Hu J, Wu J, Jin Q, Zhang L, Shen N, Shu Y, Cheng L, Zhang J, Hu G, Lv K, Jian Q, Chen H, Zhang F, Sun X. Repurposing picropodophyllin as a potential thyroid eye disease treatment via delaying mitotic clonal expansion through a patient- derived preclinical platform. Clin Transl Med. 2023 Apr;13(4):e1218. doi: 10.1002/ctm2.1218. PMID: 37012693; PMCID: PMC10070929. 7: Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O. Correction: Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1. Oncogene. 2023 Jan;42(3):253. doi: 10.1038/s41388-022-02556-8. Erratum for: Oncogene. 2008 Mar 6;27(11):1629-38. doi: 10.1038/sj.onc.1210797. PMID: 36476836. 8: Zhang J, Chen B, Li H, Wang Y, Liu X, Wong KY, Chan WN, Chan AK, Cheung AH, Leung KT, Dong Y, Pan Y, Ke H, Liang L, Zhou Z, Xiao J, Wong CC, Wu WK, Cheng AS, Ma BB, Yu J, Lo KW, Kang W; Ka Fai To. Cancer-associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2-IGF1R and Hippo-YAP1 signaling pathways. J Pathol. 2023 Feb;259(2):205-219. doi: 10.1002/path.6033. Epub 2022 Dec 17. PMID: 36373776. 9: Takata S, Sakata-Haga H, Shimada H, Tsukada T, Sakai D, Shoji H, Tomosugi M, Nakamura Y, Ishigaki Y, Iizuka H, Hayashi Y, Hatta T. LIF-IGF Axis Contributes to the Proliferation of Neural Progenitor Cells in Developing Rat Cerebrum. Int J Mol Sci. 2022 Oct 30;23(21):13199. doi: 10.3390/ijms232113199. PMID: 36361987; PMCID: PMC9659294. 10: Zhu X, Chen X, Wang G, Lei D, Chen X, Lin K, Li M, Lin H, Li D, Zheng Q. Picropodophyllin Inhibits the Proliferation of Human Prostate Cancer DU145 and LNCaP Cells via ROS Production and PI3K/AKT Pathway Inhibition. Biol Pharm Bull. 2022;45(8):1027-1035. doi: 10.1248/bpb.b21-01006. PMID: 35908886. 11: Mo HY, Wei QY, Zhong QH, Zhao XY, Guo D, Han J, Noracharttiyapot W, Visser L, van den Berg A, Xu YM, Lau ATY. Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway. Int J Mol Sci. 2022 Jul 16;23(14):7853. doi: 10.3390/ijms23147853. PMID: 35887201; PMCID: PMC9324654. 12: Sipos F, Bohusné Barta B, Simon Á, Nagy L, Dankó T, Raffay RE, Petővári G, Zsiros V, Wichmann B, Sebestyén A, Műzes G. Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response. Pathol Oncol Res. 2022 May 16;28:1610322. doi: 10.3389/pore.2022.1610322. PMID: 35651701; PMCID: PMC9148969. 13: Niu Y, Wang K, Zhu X, Zhang S, Cherepanoff S, Conway RM, Madigan MC, Lim LA, Zhu L, Murray M, Zhou F. The application of natural compounds in uveal melanoma drug discovery. J Pharm Pharmacol. 2022 May 20;74(5):660-680. doi: 10.1093/jpp/rgac009. PMID: 35532546. 14: Sun R, Tanino R, Tong X, Haque EF, Amano Y, Isobe T, Tsubata Y. Picropodophyllin inhibits the growth of pemetrexed-resistant malignant pleural mesothelioma via microtubule inhibition and IGF-1R-, caspase-independent pathways. Transl Lung Cancer Res. 2022 Apr;11(4):543-559. doi: 10.21037/tlcr-21-765. PMID: 35529797; PMCID: PMC9073748. 15: Guttman Y, Kerem Z. Dietary Inhibitors of CYP3A4 Are Revealed Using Virtual Screening by Using a New Deep-Learning Classifier. J Agric Food Chem. 2022 Mar 2;70(8):2752-2761. doi: 10.1021/acs.jafc.2c00237. Epub 2022 Feb 1. PMID: 35104412; PMCID: PMC8895463. 16: Yang L, Li K, Li W, Wang C, Liu Y, Zhang H, Pan J, Qi S, Peng J. Expression of Insulin-Like Growth Factor Type 1 Receptor Is Linked to Inflammation in Adamantinomatous Craniopharyngioma. Neuroendocrinology. 2022;112(9):917-926. doi: 10.1159/000521458. Epub 2021 Dec 13. PMID: 34915523. 17: Athapaththu AMGK, Molagoda IMN, Jayasooriya RGPT, Choi YH, Jeon YJ, Park JH, Lee BJ, Kim GY. Gamma-Aminobutyric Acid (GABA) Promotes Growth in Zebrafish Larvae by Inducing IGF-1 Expression via GABAA and GABAB Receptors. Int J Mol Sci. 2021 Oct 19;22(20):11254. doi: 10.3390/ijms222011254. PMID: 34681914; PMCID: PMC8537617. 18: Liao F, Chen Y, Wu Q, Wen J, Chen X, Wang W, Xu D, Liu M. Selective elimination of CML stem/progenitor cells by picropodophyllin in vitro and in vivo is associated with p53 activation. Biochem Biophys Res Commun. 2021 Nov 19;579:1-7. doi: 10.1016/j.bbrc.2021.09.029. Epub 2021 Sep 17. PMID: 34571387. 19: Wang L, Jiao XF, Wu C, Li XQ, Sun HX, Shen XY, Zhang KZ, Zhao C, Liu L, Wang M, Bu YL, Li JW, Xu F, Chang CL, Lu X, Gao W. Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis. Cell Death Discov. 2021 Sep 18;7(1):251. doi: 10.1038/s41420-021-00648-0. PMID: 34537816; PMCID: PMC8449784. 20: Lee SO, Kwak AW, Lee MH, Seo JH, Cho SS, Yoon G, Chae JI, Joo SH, Shim JH. Picropodophyllotoxin Induces G1 Cell Cycle Arrest and Apoptosis in Human Colorectal Cancer Cells via ROS Generation and Activation of p38 MAPK Signaling Pathway. J Microbiol Biotechnol. 2021 Dec 28;31(12):1615-1623. doi: 10.4014/jmb.2109.09012. PMID: 34528917; PMCID: PMC9705953.