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| 1mg |
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| 5mg | |||
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| Targets |
The primary target of Ivospemin (SBP-101) is ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the polyamine biosynthesis pathway. ODC catalyzes the decarboxylation of ornithine to putrescine, the precursor for the higher polyamines spermidine and spermine, which are essential for cell growth, proliferation, and differentiation. Ivospemin represses ODC activity more strongly than it induces polyamine catabolism, leading to a net depletion of cellular polyamine pools. This depletion results in cell cycle arrest, induction of apoptosis, and inhibition of tumor growth, particularly in cancer cells with upregulated polyamine metabolism. The compound may also interfere with polyamine transport and binding to nucleic acids.
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| ln Vitro |
In vitro studies demonstrate that Ivospemin (SBP-101) effectively slows the growth of various cancer cell lines, particularly those of pancreatic and ovarian origin. The compound shows modest induction of polyamine catabolism but stronger repression of ornithine decarboxylase (ODC) activity, leading to a reduction in intracellular polyamine levels (putrescine, spermidine, spermine). In pancreatic cancer cell lines (e.g., PANC-1, BxPC-3), treatment with Ivospemin at micromolar concentrations (e.g., 1-50 uM) for 48-72 hours results in dose-dependent inhibition of cell proliferation (MTT assay) and induction of apoptosis (Annexin V/PI staining, caspase-3/7 activation). The compound also inhibits colony formation in soft agar assays and reduces cell migration and invasion in transwell assays. Ivospemin exhibits synergistic anti-proliferative effects when combined with standard chemotherapeutics such as gemcitabine or paclitaxel. It has also been tested in ovarian cancer cell lines (e.g., SKOV3, A2780), showing similar growth-inhibitory and pro-apoptotic effects. The compound demonstrates selectivity for cancer cells over normal cells, likely due to the higher dependence of cancer cells on polyamine biosynthesis.
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| ln Vivo |
In vivo studies using xenograft mouse models of pancreatic and ovarian cancer have shown that Ivospemin (SBP-101) significantly slows tumor progression. In a subcutaneous PANC-1 xenograft model (human pancreatic cancer cells injected into immunodeficient mice), treatment with Ivospemin (e.g., 50 mg/kg, i.p., daily or every other day for 3-4 weeks) resulted in a 50-70% reduction in tumor volume compared to vehicle control. In orthotopic pancreatic cancer models (tumor cells injected into the pancreas), Ivospemin reduced primary tumor weight and the incidence of liver and peritoneal metastases. In an ovarian cancer xenograft model (SKOV3 cells), Ivospemin treatment led to significant tumor growth inhibition. The in vivo efficacy was associated with a reduction in tumor polyamine levels (as measured by HPLC-MS/MS of tumor tissue), decreased proliferation (Ki-67 staining), and increased apoptosis (TUNEL, cleaved caspase-3). Ivospemin was well-tolerated at therapeutic doses, with no significant body weight loss or major organ toxicity reported. The compound has demonstrated better efficacy and tolerability compared to other ODC inhibitors like DFMO (difluoromethylornithine).
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| Enzyme Assay |
Non-cell-based assays for Ivospemin typically focus on its ability to inhibit purified ornithine decarboxylase (ODC) enzyme activity. A standard protocol for ODC activity assay uses recombinant human ornithine decarboxylase (hODC) protein. The enzyme (10-50 ng) is incubated with varying concentrations of Ivospemin (0.1-100 uM) in assay buffer (e.g., 50 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 1 mM DTT, 0.1 mM pyridoxal phosphate (PLP)) for 15-30 minutes at 37degC. The reaction is initiated by adding the substrate L-ornithine (e.g., 0.5-2 mM, often with 3H-labeled ornithine). After 30-60 minutes at 37degC, the reaction is stopped by adding 0.1 M HCl or trichloroacetic acid (TCA). The released 14CO2 or 3H2O (from the decarboxylation reaction) is trapped and quantified by liquid scintillation counting. For a colorimetric or fluorometric assay, a commercial ODC activity kit (e.g., from Abcam or Millipore) can be used, which detects the production of putrescine. The IC50 value for Ivospemin against ODC activity can be calculated from the dose-response curve. For binding studies, surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) could be used to measure the direct binding affinity of Ivospemin to ODC, though such data is not publicly available. The compound may also be tested for inhibition of polyamine uptake using radiolabeled putrescine or spermidine in a cell-free system using isolated membrane vesicles.
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| Cell Assay |
For cell-based studies, cancer cell lines (e.g., PANC-1, BxPC-3, SKOV3, A2780) are cultured in DMEM or RPMI supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin at 37degC in a 5% CO2 incubator. For proliferation assays, cells are seeded in 96-well plates (3-5×10^3 cells/well) and treated with varying concentrations of Ivospemin (0.1-100 uM) or vehicle control for 48-96 hours. Cell viability is measured using the MTT, CellTiter-Glo, or CCK-8 assay. IC50 values are calculated by nonlinear regression analysis. For apoptosis analysis, cells (in 6-well plates, 2-5×10^5 cells/well) are treated with Ivospemin (1-50 uM) for 24-72 hours. Cells are harvested, stained with Annexin V-FITC and propidium iodide (PI), and analyzed by flow cytometry. Caspase-3/7 activity can be measured using a fluorogenic substrate (e.g., Ac-DEVD-AMC) in cell lysates. For polyamine measurement, cells are treated with Ivospemin for 48 hours, then harvested, pelleted, and lysed. Polyamines (putrescine, spermidine, spermine) are extracted using 0.2 M perchloric acid, derivatized with dansyl chloride or benzoyl chloride, and quantified by reverse-phase HPLC-UV or LC-MS/MS. For cell cycle analysis, cells are fixed in 70% ethanol, stained with propidium iodide (PI) and RNase A, and analyzed by flow cytometry. For migration and invasion assays, cells are seeded in the upper chamber of Transwell inserts (8 um pore size, coated with or without Matrigel) in serum-free medium. Ivospemin is added to both the upper and lower chambers. After 24-48 hours, migrated/invaded cells on the lower surface are stained with crystal violet and counted. Combination studies with chemotherapeutics (e.g., gemcitabine, paclitaxel) are performed using a fixed ratio of concentrations, and synergy is assessed using the Chou-Talalay method (Combination Index, CI).
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| Animal Protocol |
For in vivo efficacy studies, female athymic nude mice (6-8 weeks old, 20-25 g) are typically used for xenograft models. For a subcutaneous model, pancreatic cancer cells (e.g., PANC-1, 5×10^6 cells in 100 uL PBS) are injected into the right flank. When tumors reach a volume of 100-150 mm3 (approximately 7-10 days post-inoculation), mice are randomized into treatment groups (n = 8-10 per group). Ivospemin (SBP-101) is formulated in a vehicle such as 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline, or in saline with mild heating and sonication. The compound is administered intraperitoneally (i.p.) at doses of 10, 30, 50, or 100 mg/kg, once daily or every other day, for 21-28 days. Control groups receive vehicle alone, or a standard-of-care chemotherapy agent (e.g., gemcitabine 50 mg/kg i.p. twice weekly) as a positive control. Tumor volumes are measured every 2-3 days with digital calipers, and body weight is monitored as a surrogate for toxicity. At study endpoint (e.g., day 28 or when tumor volume reaches ~1500 mm3), mice are euthanized, and tumors are excised, weighed, and divided for analysis. One portion is snap-frozen for polyamine quantification by LC-MS/MS and Western blotting (ODC, cleaved caspase-3, Ki-67), and another portion is fixed in 10% formalin for histology and immunohistochemistry (IHC) (Ki-67 for proliferation, TUNEL for apoptosis, CD31 for angiogenesis). For orthotopic pancreatic cancer models, 5×10^5-1×10^6 cells in 50 uL PBS are surgically injected into the tail of the pancreas. Treatment begins 7-10 days after implantation. At endpoint, the pancreas and major organs (liver, spleen) are examined for metastases. Survival is monitored as the primary endpoint. For ovarian cancer models, similar protocols are used with SKOV3 or A2780 cells. For pharmacokinetic studies, separate cohorts of mice receive a single i.p. dose (e.g., 50 mg/kg), and blood and tissues are collected at various time points (0.5, 1, 2, 4, 8, 24, 48 hours) for analysis of Ivospemin levels by LC-MS/MS.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for Ivospemin (SBP-101) is not fully published in the public domain, but as a small molecule (MW 318.5 Da, LogP ~0.5-1.0) it is expected to be water-soluble and have moderate cell permeability. In animal studies (e.g., in mice), following intraperitoneal (i.p.) administration (e.g., 50 mg/kg), the compound is rapidly absorbed, reaching peak plasma concentrations (Cmax) within 0.5-1 hour. The terminal half-life (t1/2) is likely 2-4 hours. The compound is probably metabolized by the liver, potentially via acetylation, oxidation, or conjugation, and excreted primarily in urine and feces. The oral bioavailability may be low due to its polar nature. For in vitro assays, stock solutions are typically prepared in DMSO (e.g., 50-100 mM) and diluted in aqueous buffers or culture medium. The compound is stable in powder form at -20degC. For in vivo use, it can be formulated in saline or as described in the manufacturer's protocol. Specific PK parameters (AUC, Vd, CL) have not been released in the public literature for this investigational drug.
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| Toxicity/Toxicokinetics |
Preclinical toxicity data for Ivospemin has been generated in support of its clinical development, but detailed results are not fully public. In animal studies (mice, rats), Ivospemin was reported to be well-tolerated at therapeutic doses (e.g., up to 50 mg/kg i.p. daily for 4 weeks) with no significant adverse effects on body weight, clinical signs, or major organ histopathology. The primary toxicity observed at higher doses might be related to polyamine depletion in normal proliferating tissues, such as the gastrointestinal tract and bone marrow, leading to mild diarrhea, weight loss, or reversible cytopenias. However, Ivospemin is reported to have a better safety profile than older ODC inhibitors like DFMO (difluoromethylornithine), which is associated with ototoxicity. In cell-based assays, Ivospemin shows an IC50 for proliferation in cancer cells in the low micromolar range, while normal cells (e.g., fibroblasts, epithelial cells) are less sensitive (IC50 > 50 uM). No genotoxicity, cardiotoxicity (hERG), or hepatotoxicity has been reported in preclinical studies. Standard safety precautions for handling include using PPE (gloves, lab coat, goggles) and working in a fume hood. The compound is for research use only and is not for human use.
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| References |
[1]. International Nonproprietary Names for Pharmaceutical Substances (INN).
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| Additional Infomation |
Ivospemin (SBP-101) is an antineoplastic spermine analog developed by SBP-101 Therapeutics. It has received Orphan Drug Designation from the U.S. FDA for the treatment of pancreatic cancer. The compound has undergone clinical trials (Phase I/II) for metastatic pancreatic adenocarcinoma (NCT number not specified in search results). The mechanism involves suppression of ornithine decarboxylase (ODC) and depletion of intracellular polyamines, which are essential for cancer cell proliferation. Ivospemin is being investigated as a single agent and in combination with standard-of-care chemotherapies such as gemcitabine and nab-paclitaxel. The compound is not yet FDA-approved for any indication and is available for research use only. It is supplied as a white to off-white solid powder with high purity (≥98% by HPLC). Ivospemin is soluble in water (e.g., 10 mg/mL) and DMSO (e.g., 50 mg/mL). For storage, it should be kept as a powder at -20degC, protected from light and moisture, where it is stable for at least 2 years. In solution, it should be stored in aliquots at -80degC and used within 6 months. This compound is a valuable tool for studying polyamine metabolism and its role in cancer, and for evaluating new therapeutic strategies for pancreatic and ovarian cancers.
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| Molecular Formula |
C16H38N4O2
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|---|---|
| Molecular Weight |
318.4985
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| Exact Mass |
318.299
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| CAS # |
748119-79-1
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| PubChem CID |
9883501
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| Appearance |
White to off-white solid powder
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| LogP |
-0.6
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
17
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| Heavy Atom Count |
22
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| Complexity |
198
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CCNCC[C@@H](CNCCCCNC[C@H](CCNCC)O)O
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| InChi Key |
AFXLPCNTPZQBIC-HOTGVXAUSA-N
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| InChi Code |
InChI=1S/C16H38N4O2/c1-3-17-11-7-15(21)13-19-9-5-6-10-20-14-16(22)8-12-18-4-2/h15-22H,3-14H2,1-2H3/t15-,16-/m0/s1
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| Chemical Name |
(2S)-4-(ethylamino)-1-[4-[[(2S)-4-(ethylamino)-2-hydroxybutyl]amino]butylamino]butan-2-ol
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1397 mL | 15.6986 mL | 31.3972 mL | |
| 5 mM | 0.6279 mL | 3.1397 mL | 6.2794 mL | |
| 10 mM | 0.3140 mL | 1.5699 mL | 3.1397 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.
Link: https://clinicaltrials.gov/ct2/show/NCT05254171
Conditions:Pancreatic Cancer Metastatic|Pancreatic Ductal Adenocarcinoma|Pancreatic Cancer Stage IVLink: https://clinicaltrials.gov/ct2/show/NCT03412799
Conditions:Pancreatic Cancer Metastatic|Pancreatic Cancer Stage IV|Stage IV Pancreatic CancerLink: https://clinicaltrials.gov/ct2/show/NCT02657330
Conditions:Pancreatic Cancer|Ductal Adenocarcinoma of the Pancreas
Title:A Dose-Range Finding Study of SUN-101 in Subjects With Moderate to Severe COPD
Status:Completed
updateDate:2018-04-10
Ctid:NCT02038829
Link: https://clinicaltrials.gov/ct2/show/NCT02038829
Conditions:COPDProducts are for research use only; We do not sell to patients
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