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| Targets |
LMP744 HCl targets topoisomerase I (TOP1), an essential nuclear enzyme that relieves torsional stress in DNA during replication and transcription by creating transient single-strand breaks. LMP744 functions as a non-camptothecin TOP1 inhibitor. It acts by intercalating into DNA, thereby stabilizing the otherwise transient TOP1-DNA cleavage complex. This "poisoning" of the enzyme converts TOP1 into a cellular toxin, as the stabilized cleavage complexes collide with replication forks, leading to the formation of irreversible DNA double-strand breaks and ultimately triggering cell death. Consistent with TOP1 poisoning, protein-linked DNA breaks are detected in cells treated with LMP744 at nanomolar concentrations. This mechanism is distinct from that of camptothecin, allowing LMP744 to overcome multidrug resistance.
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| ln Vitro |
LMP744 (MJ-III-65) has a GI50 value of 0.1 μM for NCI60 cells[2]. In the S and G2 phases of the cell cycle, dose-dependent cell accumulation is induced by LMP744 (0.1–5 μM, 3 days) [2].
In vitro, LMP744 HCl demonstrates potent anticancer activity. In the NCI60 cell line panel, it shows a GI50 value of 0.1 μM, indicating broad-spectrum antiproliferative activity. The compound induces a dose-dependent accumulation of cells in the S and G2 phases of the cell cycle at concentrations ranging from 0.1 to 5 μM. It produces persistent topoisomerase I cleavage complexes and can overcome multidrug resistance. Studies in human cell cultures have found LMP744 to be cytotoxic, with limited cross-resistance observed in camptothecin-resistant cell lines. These in vitro activities confirm its potent TOP1 inhibitory and anticancer effects. |
| ln Vivo |
When given as a weekly intravenous bolus for four weeks in nude mice, LMP744 (MJ-III-65) (10-50 mg/kg) exhibits moderate effectiveness against human A253 and FaDu tumor xenografts with no obvious harm [1].
In vivo, LMP744 HCl has demonstrated antitumor activity in mouse tumor xenograft models. In athymic nude mice bearing human A253 and FaDu head and neck xenografts, intravenous bolus injections of LMP744 at doses of 10, 25, or 50 mg/kg/week for four weeks showed moderate activity against the tumors with no significant toxicity. These in vivo data support its potential as an anticancer agent. |
| Enzyme Assay |
Non-cell-based assays for LMP744 HCl include DNA intercalation assays and topoisomerase I (TOP1) inhibition assays. DNA intercalation is assessed using techniques such as ethidium bromide displacement assays, where the compound's ability to displace ethidium bromide from DNA is measured by fluorescence spectroscopy. TOP1 inhibition is assessed using purified TOP1 enzyme and a plasmid DNA substrate. The compound is incubated with TOP1 and plasmid DNA, and the reaction products are analyzed by agarose gel electrophoresis to detect the formation of nicked or linear DNA, indicative of TOP1 poisoning.
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| Cell Assay |
Cytotoxicity assay[2]
Cell Types: P388 and P388 Top1-deficient mouse leukemia cells. Tested Concentrations: 0.1-100 μM Incubation Duration: 3 days Experimental Results: Induces dose-dependent accumulation of cells in S and G2 phases of the cell cycle. Cellular assays for LMP744 HCl utilize various cancer cell lines, including the NCI60 panel. Cells are treated with the compound at various concentrations for specified durations (e.g., 3 days). Cell proliferation and viability are assessed using standard assays such as SRB or MTT to determine GI50 values. Cell cycle analysis is performed by flow cytometry after propidium iodide staining to confirm S and G2 phase accumulation. The formation of protein-linked DNA breaks, a hallmark of TOP1 poisoning, is detected using the RADAR (rapid approach to DNA adduct recovery) assay or by measuring the amount of TOP1 covalently linked to DNA. |
| Animal Protocol |
Animal/Disease Models: Athymic nude mice (nu/nu, female, 20-25 g, 8-12 weeks old) were transplanted with A253 and FaDu human head and neck xenografts [1].
Doses: 10, 25, or 50 mg/kg/week, 4 weeks Route of Administration: intravenous (iv) (iv)bolus injection via tail vein Experimental Results: Moderate activity against human A253 and FaDu tumor xenografts with no significant toxicity. In vivo animal models for LMP744 HCl include xenograft studies in athymic nude mice. Mice bearing human A253 or FaDu head and neck tumor xenografts are treated with LMP744 via intravenous bolus injection at doses of 10, 25, or 50 mg/kg/week for four weeks. Tumor growth is monitored by caliper measurements. Toxicity is assessed by monitoring body weight, and tumor tissues may be collected for histopathological examination and analysis of TOP1 cleavage complexes. Detailed protocols are reported in the literature. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of LMP744 HCl include a molecular weight of 488.92 g/mol and molecular formula C24H25ClN2O7. The CAS number is 308246-57-3. The compound is a small molecule DNA intercalator and TOP1 inhibitor. It is soluble in DMSO. The compound appears as a light brown to brown solid powder. Detailed PK parameters such as half-life and bioavailability are not extensively reported, but intravenous administration is used in vivo.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for LMP744 HCl are not extensively reported, but in vivo studies show no significant toxicity at doses up to 50 mg/kg/week in mice. As a research compound, its safety profile would need to be established through standard preclinical toxicity assessments. The compound is supplied for research use only. Given its mechanism of TOP1 inhibition and DNA intercalation, potential genotoxicity and effects on rapidly dividing normal tissues would be key safety considerations.
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| References |
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| Additional Infomation |
LMP744 HCl is also known as MJ-III65 hydrochloride, NSC706744 hydrochloride, and Mj-III-65. It has CAS number 308246-57-3. It is a synthetic indenoisoquinoline small molecule that functions as a DNA intercalator and a potent non-camptothecin topoisomerase I (TOP1) inhibitor. It produces persistent topoisomerase I cleavage complexes and can overcome multidrug resistance. It shows potent antitumor activity in vitro and in vivo. It is for research use only.**
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| Molecular Formula |
C24H25CLN2O7
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| Molecular Weight |
488.92
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| Exact Mass |
488.135
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| CAS # |
308246-57-3
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| Related CAS # |
LMP744;308246-52-8
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| PubChem CID |
397887
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| Appearance |
Light brown to brown solid powder
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| LogP |
3.123
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
34
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| Complexity |
802
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
POXWLZDVWCKKEX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H24N2O7.ClH/c1-30-17-8-13-16(11-18(17)31-2)24(29)26(6-3-4-25-5-7-27)22-14-9-19-20(33-12-32-19)10-15(14)23(28)21(13)22/h8-11,25,27H,3-7,12H2,1-2H31H
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| Chemical Name |
6-(3-((2-hydroxyethyl)amino)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4',5'
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| Synonyms |
Mj-III65, NSC706744Mj-III-65, NSC-706744 LMP744 HCl LMP 744 HCl
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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, 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 : ~105 mg/mL (~214.76 mM)
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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 | 2.0453 mL | 10.2266 mL | 20.4532 mL | |
| 5 mM | 0.4091 mL | 2.0453 mL | 4.0906 mL | |
| 10 mM | 0.2045 mL | 1.0227 mL | 2.0453 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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