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| Targets |
Leptomycin B targets CRM1 (chromosome region maintenance 1), also known as exportin-1, which is the primary mediator of nuclear export for proteins containing nuclear export signals (NES). The compound binds covalently to CRM1, inhibiting its ability to transport proteins and RNAs from the nucleus to the cytoplasm. By blocking CRM1, Leptomycin B prevents the nuclear export of key regulatory proteins including HIV-1 Rev, MAPK/ERK, NF-κB/IκB, and p53. This leads to nuclear accumulation of these proteins, affecting cell cycle regulation, apoptosis, and viral replication. The compound also shows antifungal activity.
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| ln Vitro |
Leptomycin B (LMB) has IC50 values ranging from 0.1 to 10 nM, making it extremely effective against a wide range of cancer cell types in vitro. After 72 hours of exposure, leptomycin B (LMB) inhibits SiHa, HCT-116, and SKNSH cells with IC50 values of 0.4, 0.3, and 0.4 nM, respectively [2]. In A549 and H460 cell lines, leptomycin B (LMB) (0.5 nM) has a synergistic impact against gefitinib (0–32 μM)-induced cytotoxicity. When gefitinib (0–32 μM) and leptomycin B (0.5 nM) were administered concurrently, A549 displayed synergistic cytotoxic effects at 24 and 48 hours, as opposed to gefitinib alone [3].
In vitro studies demonstrate that Leptomycin B inhibits nucleo-cytoplasmic translocation of molecules such as the HIV-1 Rev protein and Rev-dependent export of mRNA. The addition of very low amounts of Leptomycin B to fibroblasts causes accumulation of MEK in the nucleus. Leptomycin B blocks the cell cycle and shows potent anti-tumor activity. The compound inhibits the nuclear export of many proteins including HIV-1 Rev, MAPK/ERK, and NF-κB/IκB, and inhibits the inactivation of p53. The p38 MAPK/VEGF axis may be one of therapeutic targets for leptomycin B in neurological diseases. |
| ln Vivo |
In vivo, leptomycin B (LMB) is not well tolerated. The maximum tolerated dosage (MTD) of LMB (single intravenous injection) in tumor-bearing HCT-116 mice was 2.5 mg/kg. Leptomycin B's poor in vivo efficacy is caused by off-target effects; in contrast, our nuclear export inhibitors (NEIs) appear to be more well tolerated in vivo while maintaining strong CRM1 inhibition [4].
In vivo studies show that Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells. The compound exhibits antitumor activity in various cancer models. As a CRM1 inhibitor, Leptomycin B has been used to study the role of nuclear export in cancer, viral infections, and other diseases. The compound's ability to block nuclear export of key regulatory proteins makes it a valuable tool for studying nucleo-cytoplasmic trafficking. Further in vivo studies are warranted to fully characterize the compound's therapeutic potential. |
| Enzyme Assay |
The in vitro CRM1 binding assay for Leptomycin B involves measuring CRM1 binding affinity using biochemical or cell-based assays. Recombinant CRM1 is incubated with varying concentrations of Leptomycin B (0.1 nM-10 μM). Binding is assessed by surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). For functional assays, cells expressing GFP-tagged nuclear export signal (NES) proteins are treated with Leptomycin B and nuclear export is assessed by fluorescence microscopy. HIV-1 Rev-dependent mRNA export is measured by qPCR of cytoplasmic mRNA. p53 stability is assessed by Western blot. IC50 values are determined from dose-response curves.
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| Cell Assay |
Cell viability assay [3]
Cell Types: Non-small cell lung cancer (NSCLC) cell lines A549 and H460 Tested Concentrations: 0.5 nM Incubation Duration: 24 and 48 hrs (hours) Experimental Results: The IC50 of gefitinib at 48 hrs (hours) is 32.0±2.5 μM, while with After combination with 0.5 nM Leptomycin B, its concentration was Dramatically diminished to 25.0±2.1 μM. The significant synergistic cytotoxic effect of co-treatment of 0.5 nM Leptomycin B with gefitinib was also confirmed in the H460 cell line. Cell viability assay[3] Cell Types: A549 Tested Concentrations: 0.5 nM Incubation Duration: 48 hrs (hours) Experimental Results: 0.5 nM Leptomycin B plus gefitinib or gefitinib alone diminished p-EGFR(Tyr1068) expression compared to control . p-Akt (Ser473) was inhibited by gefitinib treatment in a dose-response manner, but was enhanced by combined gefitinib + linbumycin B treatment compared with gefitinib alone. A549 treated with gefitinib + light mycin B had higher expression of p-Erk1/2 (Thr202/Tyr204) than A549 treated with gefitinib alone. In vitro cellular assays for Leptomycin B typically use various cell lines including fibroblasts, cancer cells, and HIV-infected cells. Cells are cultured in appropriate media and treated with the compound at concentrations of 0.1 nM-1 μM for 1-24 hours. Nuclear export of proteins (e.g., HIV-1 Rev, MAPK/ERK, NF-κB) is assessed by immunofluorescence or subcellular fractionation followed by Western blot. Cell cycle analysis is performed by flow cytometry. Apoptosis is evaluated using caspase-3/7 activity assays and Annexin V staining. Cell viability is assessed using MTT or CCK-8 assays. HIV-1 replication is assessed by measuring p24 antigen or viral RNA. |
| Animal Protocol |
In vivo animal studies for Leptomycin B involve mouse models of cancer or viral infection. Mice bearing tumors are treated with the compound via intraperitoneal or intravenous injection at doses of 0.1-1 mg/kg on a scheduled basis for 1-4 weeks. Tumor volume is measured regularly and tumor weight is determined at necropsy. For resistance studies, gefitinib-resistant lung cancer models are used. CRM1 inhibition in tumor tissues is assessed by nuclear accumulation of NES-containing proteins. Survival analysis is performed. Pharmacodynamic studies evaluate target engagement and pathway modulation.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Leptomycin B are characterized by its potent activity at very low concentrations. The compound has a molecular weight of 540.75 and molecular formula of C33H48O6. It is soluble in ethanol and other organic solvents. The compound should be stored at -20°C for long-term preservation. Leptomycin B is typically used at nanomolar concentrations due to its high potency as a CRM1 inhibitor. Further studies on plasma half-life, clearance, and tissue distribution are needed.
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| Toxicity/Toxicokinetics |
Toxicological data for Leptomycin B indicates potent biological activity with potential toxicity at higher doses. As an antifungal antibiotic and CRM1 inhibitor, the compound can affect multiple cellular processes. The compound is for research use only and not for human therapeutic applications. Standard safety precautions should be followed when handling. For detailed toxicity information, safety data sheets should be consulted.
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| References |
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| Additional Infomation |
Leptomycin B is a Leptomycin with a (2E, 10E, 12E, 16Z, 18E) double bond configuration and an ethyl substituent at position 17. It is an antifungal agent and a bacterial metabolite. It is a Leptomycin and a hydroxy polyunsaturated fatty acid. Its function is related to tetracosanoic acid. Leptomycin B has been reported in Streptomyces, and relevant data are available for reference.
Leptomycin B (LMB, CI 940) is a research compound with CAS number 87081-35-4. Its molecular formula is C33H48O6 and molecular weight is 540.75. The compound is a potent and specific inhibitor of CRM1/exportin-1, blocking nuclear export. It exhibits antiviral, antifungal, and antitumor activities. The compound blocks nuclear export of HIV-1 Rev, MAPK/ERK, NF-κB, and other proteins. It has been used to study nucleo-cytoplasmic trafficking and CRM1 function. This compound has not been approved by the FDA and is strictly for research purposes only. |
| Molecular Formula |
C33H48O6
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|---|---|
| Molecular Weight |
540.741
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| Exact Mass |
540.345
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| CAS # |
87081-35-4
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| PubChem CID |
6917907
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| Appearance |
White to yellow <41°C powder,>44°C liquid
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
725.8±60.0 °C at 760 mmHg
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| Melting Point |
41-44ºC
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| Flash Point |
224.8±26.4 °C
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| Vapour Pressure |
0.0±5.3 mmHg at 25°C
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| Index of Refraction |
1.542
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| LogP |
6.66
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
15
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| Heavy Atom Count |
39
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| Complexity |
1020
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| Defined Atom Stereocenter Count |
7
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| SMILES |
C(/[C@@H]1OC(=O)C=C[C@@H]1C)=C\C(\CC)=C/[C@H](C)C/C=C/C(/C)=C/[C@@H](C)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C/C(/C)=C/C(=O)O
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| InChi Key |
YACHGFWEQXFSBS-XYERBDPFSA-N
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| InChi Code |
InChI=1S/C33H48O6/c1-9-28(14-15-29-24(5)13-16-31(36)39-29)19-22(3)12-10-11-21(2)17-25(6)32(37)27(8)33(38)26(7)18-23(4)20-30(34)35/h10-11,13-17,19-20,22,24-27,29,33,38H,9,12,18H2,1-8H3,(H,34,35)/b11-10+,15-14+,21-17+,23-20+,28-19-/t22-,24+,25-,26+,27-,29+,33-/m1/s1
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| Chemical Name |
(2E,5S,6R,7S,9R,10E,12E,15R,16Z,18E)-17-ethyl-6-hydroxy-3,5,7,9,11,15-hexamethyl-19-[(2S,3S)-3-methyl-6-oxo-2,3-dihydropyran-2-yl]-8-oxononadeca-2,10,12,16,18-pentaenoic acid
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| Synonyms |
LMB NSC364372Elactocin NSC-364372Leptomycin B
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
DMSO : ≥ 100 mg/mL (~184.94 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (4.62 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8493 mL | 9.2466 mL | 18.4932 mL | |
| 5 mM | 0.3699 mL | 1.8493 mL | 3.6986 mL | |
| 10 mM | 0.1849 mL | 0.9247 mL | 1.8493 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.
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