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| Targets |
Chst15-IN-34 targets Chst15 (carbohydrate sulfotransferase 15), the sulfotransferase responsible for the biosynthesis of chondroitin sulfate-E (CS-E). CS-E is a sulfated glycosaminoglycan that contributes to the inhibitory activity of chondroitin sulfate proteoglycans (CSPGs) in the central nervous system. By inhibiting Chst15, the compound reduces CS-E sulfation and CSPG inhibitory activity, promoting neuronal repair and regeneration.
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| ln Vitro |
Neu7 astrocytes exposed to 25 μM of Chst15-IN-1 for 24 hours show sulfotransferases to be preferred over a wide range of reactive cysteine-containing proteins. Chst15-IN-1 (10 and 25 μM; Neu7 astrocytes) exhibits a notable reduction in cell surface CS-E expression that is dose-dependent [1].
In vitro, Chst15-IN-34 (referred to as Chst15-IN-1 in the reference) was tested in Neu7 astrocytes exposed to 25 μM for 24 hours, showing preferential inhibition of sulfotransferases over a wide range of reactive cysteine-containing proteins. At 10 and 25 μM in Neu7 astrocytes, the compound exhibits a notable reduction in cell surface CS-E expression that is dose-dependent. This demonstrates its potent and selective inhibition of Chst15-mediated CS-E sulfation. |
| ln Vivo |
Chst15-IN-1 (3.0 mg/kg; iv) has a short terminal half-life of 1.6 hours, a moderate volume of distribution of 0.97 L/kg, and a moderate clearance of 21 mL/min/kg [1].
In vivo, Chst15-IN-34 (Chst15-IN-1) was administered intravenously to rats at 3.0 mg/kg for pharmacokinetic analysis. The compound demonstrated a short terminal half-life of 1.6 hours, a moderate volume of distribution of 0.97 L/kg, and a moderate clearance of 21 mL/min/kg. These PK properties suggest that the compound has limited systemic exposure following IV administration, which may be suitable for localized applications in the central nervous system. |
| Enzyme Assay |
In vitro enzyme assays for Chst15 inhibition typically use recombinant Chst15 enzyme and a suitable substrate such as chondroitin sulfate or a synthetic acceptor. The assay measures the transfer of sulfate from the donor (PAPS - 3'-phosphoadenosine-5'-phosphosulfate) to the acceptor substrate. Chst15-IN-34 is incubated with the enzyme and substrates at varying concentrations, and the sulfation product is quantified using radiometric (³⁵S-PAPS) or HPLC-based methods. IC50 values are calculated from dose-response curves. Selectivity is assessed by testing against other sulfotransferases.
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| Cell Assay |
Cellular assays for Chst15 inhibition typically use Neu7 astrocytes or other cell lines expressing Chst15. Cells are treated with Chst15-IN-34 at various concentrations (e.g., 10-25 μM) for 24 hours. Cell surface CS-E expression is measured using flow cytometry with CS-E-specific antibodies (e.g., anti-CS-E monoclonal antibodies). The reduction in CS-E expression is quantified as mean fluorescence intensity. Dose-response curves are generated to calculate IC50 values. Selectivity is assessed by measuring other GAG sulfation levels.
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| Animal Protocol |
Animal/Disease Models: Rat
Doses: 3.0 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)injection Experimental Results: moderate clearance 21 mL/min/kg, moderate volume of distribution 0.97 L/kg, terminal The short half-life is 1.6 hrs (hrs (hours)). In vivo animal studies for Chst15 inhibitors typically use rat models of spinal cord injury or other CNS injury where CSPG inhibition is therapeutic. Animals are administered Chst15-IN-34 via intrathecal or intravenous injection, and neuronal regeneration or functional recovery is assessed. For PK studies, rats are administered the compound intravenously at 3.0 mg/kg, and blood samples are collected at various time points for plasma concentration analysis by LC-MS/MS. |
| ADME/Pharmacokinetics |
Chst15-IN-34 (Chst15-IN-1) was evaluated in rat PK studies following intravenous administration at 3.0 mg/kg. Key PK parameters include: terminal half-life of 1.6 hours, volume of distribution of 0.97 L/kg, and clearance of 21 mL/min/kg. These parameters indicate moderate distribution and clearance, with a relatively short half-life. The compound's PK properties suggest that it may require frequent dosing or continuous administration for sustained target inhibition in vivo.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies of Chst15-IN-34 would typically include acute toxicity in rodents, repeated-dose toxicity, and genotoxicity assessments. As a covalent inhibitor, special attention would be paid to potential off-target reactivity with cysteine-containing proteins. In vitro studies showed that Chst15-IN-1 preferentially inhibits sulfotransferases over a wide range of reactive cysteine-containing proteins, suggesting a favorable selectivity profile. Further toxicity data are limited as the compound is in early research stages.
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| References | |
| Additional Infomation |
Chst15-IN-34 is a research compound that acts as a potent reversible covalent inhibitor of Chst15, the sulfotransferase responsible for CS-E biosynthesis. By inhibiting CS-E sulfation, it reduces CSPG inhibitory activity, which is promising for stimulating neuronal repair after CNS injury. The compound demonstrates dose-dependent reduction in cell surface CS-E expression in vitro and has been evaluated in rat PK studies. It is available for research use only and is not approved for therapeutic applications.
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| Molecular Formula |
C17H11BRCL2N2O3
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| Molecular Weight |
442.090841531754
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| Exact Mass |
439.933
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| CAS # |
2158198-77-5
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| PubChem CID |
5794800
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
5.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
25
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| Complexity |
565
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| Defined Atom Stereocenter Count |
0
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| SMILES |
BrC1C(=C(C=C(/C=C(\C#N)/C(NC2C=CC(=CC=2Cl)Cl)=O)C=1)OC)O
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| InChi Key |
RRFHFNDPXNWVTL-ONNFQVAWSA-N
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| InChi Code |
InChI=1S/C17H11BrCl2N2O3/c1-25-15-6-9(5-12(18)16(15)23)4-10(8-21)17(24)22-14-3-2-11(19)7-13(14)20/h2-7,23H,1H3,(H,22,24)/b10-4+
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| Chemical Name |
(E)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-2-cyano-N-(2,4-dichlorophenyl)prop-2-enamide
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| Synonyms |
Chst15 IN 34; Chst15IN34; Chst15-IN-34
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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) |
DMSO : ~50 mg/mL (~113.10 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 | 2.2620 mL | 11.3099 mL | 22.6198 mL | |
| 5 mM | 0.4524 mL | 2.2620 mL | 4.5240 mL | |
| 10 mM | 0.2262 mL | 1.1310 mL | 2.2620 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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