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| Targets |
The primary molecular targets of MP-A08 are sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2). These enzymes catalyze the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P), a bioactive lipid that promotes cell proliferation, survival, and angiogenesis. By competitively inhibiting the ATP-binding site of these kinases, MP-A08 reduces the production of S1P. This leads to the suppression of S1P-mediated signaling pathways, which are often overactive in cancer cells, resulting in the inhibition of cell growth and the induction of apoptosis.
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| ln Vitro |
By preventing tumor angiogenesis and causing tumor cell apoptosis, MP-A08 inhibits pro-proliferative signaling pathways, causes mitochondria-associated apoptosis in an SK-dependent manner, and decreases the growth of human lung adenocarcinoma tumors in mouse xenograft models. Both cell types exhibit decreased EC barrier integrity in vitro as a result of MP-A08's inhibition of SphK2. [2]
In vitro, MP-A08 is a potent inhibitor of SphK1 and SphK2. Its Ki values of 6.9 µM for SphK1 and 27 µM for SphK2 demonstrate its inhibitory activity. The compound is highly selective for these kinases, with little affinity for other kinases, which is a key feature of its pharmacological profile. In cell-based studies, MP-A08 has been shown to inhibit the growth of various cancer cell lines. It induces SK-dependent mitochondrial apoptosis and blocks pro-proliferative signaling pathways. It also reduces the integrity of the endothelial cell (EC) barrier in vitro by inhibiting SphK2. |
| ln Vivo |
Mice xenografts of human lung tumors are inhibited in development by MP-A08.
In vivo, MP-A08 has demonstrated antitumor activity in mouse xenograft models. Specifically, it has been shown to slow the growth of human lung adenocarcinoma tumors. Its mechanism of action in vivo involves the induction of tumor cell apoptosis and the inhibition of tumor angiogenesis. By blocking the production of S1P, MP-A08 disrupts the tumor microenvironment and inhibits the formation of new blood vessels, which are essential for tumor growth and metastasis. Its efficacy in these models highlights its potential as an anticancer agent. |
| Enzyme Assay |
For in vitro enzyme assays, the activity of MP-A08 is assessed by measuring its inhibition of sphingosine kinase activity. Standard protocols involve incubating the enzyme (SphK1 or SphK2) with its substrate, sphingosine, and ATP in the presence of varying concentrations of MP-A08. The amount of S1P produced is then measured, often using radioisotope-labeled ATP or mass spectrometry. The reduction in S1P production in the presence of the inhibitor is used to calculate the inhibition constant (Ki).
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| Cell Assay |
Cell-based in vitro assays for MP-A08 involve treating cancer cell lines with the compound and assessing its effects on cell viability, proliferation, and signaling pathways. Cells are typically treated with MP-A08 at concentrations ranging from 1 to 50 µM for 24 to 72 hours. Cell viability is measured using MTT or CellTiter-Glo assays. The induction of apoptosis can be assessed by Annexin V staining or by measuring caspase activity. The inhibition of S1P production and downstream signaling can be confirmed by measuring S1P levels or by Western blotting for phosphorylated signaling proteins.
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| Animal Protocol |
In vivo animal experiments for MP-A08 are typically conducted in xenograft models. Human cancer cells, such as lung adenocarcinoma cells, are implanted subcutaneously into immunodeficient mice. When tumors reach a certain size, MP-A08 is administered, often via intraperitoneal injection, at various doses. Tumor growth is monitored over time, and endpoints include tumor volume, tumor weight, and survival. The compound's anti-angiogenic effects can be assessed by staining tumor sections for blood vessels.
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| ADME/Pharmacokinetics |
Pharmacokinetic (PK) data for MP-A08 are not extensively detailed in the provided search results. As a small molecule with a molecular weight of 519.64 g/mol, it is likely to have some oral bioavailability, though it may be administered parenterally in animal studies. Its distribution, metabolism, and excretion would be typical of a lipophilic drug. Specific PK parameters, such as half-life, Cmax, and clearance, would be determined in dedicated PK studies.
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| Toxicity/Toxicokinetics |
Toxicology data for MP-A08 are not provided in the search results. As a research compound, its safety profile would be evaluated in preclinical studies to assess potential off-target effects and general toxicity. Its selectivity for SphK1 and SphK2 over other kinases suggests that it may have a more favorable safety profile compared to less selective inhibitors. However, specific toxicological endpoints, such as acute toxicity, genotoxicity, or organ-specific toxicity, are not detailed.
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| References | |
| Additional Infomation |
MP-A08 is a sulfonamide compound composed of two 4-methyl-N-phenylbenzenesulfonamide units linked at the 2-position by an imine linker. It is an ATP-competitive sphingosine kinase inhibitor, targeting SK1 and SK2 (Ki values of 27 μM and 6.9 μM, respectively), and possesses anticancer properties. It can be used as an antitumor drug, an apoptosis inducer, an angiogenesis inhibitor, and an EC 2.7.1.91 (sphingosine kinase) inhibitor. It is a sulfonamide compound belonging to the toluene class of compounds and contains an imine group.
In summary, MP-A08 is a highly selective, ATP-competitive inhibitor of sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2). It inhibits SphK1 with a Ki of 6.9 µM and SphK2 with a Ki of 27 µM. By blocking the production of S1P, it inhibits tumor cell proliferation, induces apoptosis, and suppresses angiogenesis. Its antitumor activity has been demonstrated in mouse xenograft models. MP-A08 is a valuable tool for studying the role of sphingosine kinases in cancer and other diseases. It is available for research use only and is not approved for therapeutic applications. |
| Molecular Formula |
C27H25N3O4S2
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|---|---|
| Molecular Weight |
519.63
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| Exact Mass |
519.128
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| CAS # |
219832-49-2
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| PubChem CID |
420266
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
717.1±70.0 °C at 760 mmHg
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| Flash Point |
387.5±35.7 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.634
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| LogP |
5.31
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
36
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| Complexity |
925
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC=C2C=NC3=CC=CC=C3NS(=O)(=O)C4=CC=C(C=C4)C
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| InChi Key |
FLDBNMYJUMAXDQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H25N3O4S2/c1-20-11-15-23(16-12-20)35(31,32)29-25-8-4-3-7-22(25)19-28-26-9-5-6-10-27(26)30-36(33,34)24-17-13-21(2)14-18-24/h3-19,29-30H,1-2H3
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| Chemical Name |
4-methyl-N-[2-[[2-[(4-methylphenyl)sulfonylamino]phenyl]iminomethyl]phenyl]benzenesulfonamide
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| Synonyms |
MPA08 MP A08 MP-A08
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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: This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| 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 : ≥ 50 mg/mL (~96.22 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.81 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 (4.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9244 mL | 9.6222 mL | 19.2445 mL | |
| 5 mM | 0.3849 mL | 1.9244 mL | 3.8489 mL | |
| 10 mM | 0.1924 mL | 0.9622 mL | 1.9244 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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