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K145 (K-145) is a novel, potent and selective SphK2 (sphingosine kinase-2) inhibitor with anticancer effects. It inhibits SphK2 with an IC50 of 4.30±0.06 μM and exhibits no inhibition against SphK1 at concentrations up to 10 μM. As a selective sphingosine kinase-2 (SphK2) inhibitor, K145 has anticancer activity and inhibited the activity of SphK2 in a dose-dependent manner. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors.
| ln Vitro |
K145 (0-10 µM; 24-72 hours; U937 cells) therapy greatly reduces the proliferation of U937 cells in a concentration-dependent manner [1]. K145 (10 µM; 24 hours; U937 cells) treatment effectively promoted apoptosis in U937 cells [1]. K145 (4-8 µM; 3 hours; U937 cells) treatment lowers ERK and Akt phosphorylation [1]. K145 (10 µM) therapy resulted in a decrease in total cellular S1P but had no significant effect on ceramide levels [1].
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| ln Vivo |
The treatment of BALB/c-nu mice with K145 (50 mg/kg; oral gavage; daily; for 15 days) dramatically slowed the formation of U937 tumors in nude mice [1].
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| Cell Assay |
Cell viability assay [1]
Cell Types: U937 cells Tested Concentrations: 0 µM, 4 µM, 6 µM, 8 µM, 10 µM Incubation Duration: 24 hrs (hours), 48 hrs (hours), 72 hrs (hours) Experimental Results: Dramatically inhibited the growth of U937 cells at a certain concentration Growth-dependent manner. Apoptosis analysis [1] Cell Types: U937 Cell Tested Concentrations: 10 µM Incubation Duration: 24 hrs (hours) Experimental Results: Dramatically induced apoptosis in U937 cells. Western Blot Analysis[1] Cell Types: U937 Cell Tested Concentrations: 4 µM, 8 µM Incubation Duration: 3 hrs (hours) Experimental Results: diminished phosphorylated ERK and Akt. |
| Animal Protocol |
Animal/Disease Models: BALB/c-nu (nude) mice injected with U937 cells [1]
Doses: 50 mg/kg Route of Administration: po (oral gavage); daily; 15 days Experimental Results: po (oral gavage); daily; 50 mg/kg dose It inhibited U937 tumor growth for 15 days and no obvious toxicity was observed. |
| References |
| Molecular Formula |
C₁₈H₂₄N₂O₃S
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|---|---|
| Molecular Weight |
348.46
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| Exact Mass |
348.151
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| CAS # |
1309444-75-4
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| Related CAS # |
K145 hydrochloride;1449240-68-9
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| PubChem CID |
71714682
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.974
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
24
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| Complexity |
459
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(N(CCN)C/1=O)SC1=C/CCC2=CC=C(OCCCC)C=C2
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| InChi Key |
MPZXLTZVPUSTFY-SOFYXZRVSA-N
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| InChi Code |
InChI=1S/C18H24N2O3S/c1-2-3-13-23-15-9-7-14(8-10-15)5-4-6-16-17(21)20(12-11-19)18(22)24-16/h6-10H,2-5,11-13,19H2,1H3/b16-6-
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| Chemical Name |
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
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| Synonyms |
K145 K-145 K 145
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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 | 2.8698 mL | 14.3488 mL | 28.6977 mL | |
| 5 mM | 0.5740 mL | 2.8698 mL | 5.7395 mL | |
| 10 mM | 0.2870 mL | 1.4349 mL | 2.8698 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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