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| Targets |
The primary target of NCT-504 is phosphatidylinositol-5-phosphate 4-kinase gamma (PIP4Kγ), a lipid kinase involved in phosphoinositide metabolism and cellular signaling. The compound acts as a selective allosteric inhibitor with an IC50 of 15.8 μM. PIP4Kγ is implicated in pathways relevant to neurodegenerative disorders, particularly Huntington's disease. NCT-504 may also target other related kinases, but its selectivity for PIP4Kγ is its defining feature.
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| ln Vitro |
NCT-504 does not reduce PIP4Kγ's intrinsic ATP hydrolytic activity when PI5P substrate is not present[1]. NCT-504 modestly inhibits PIP4Kalpha phosphorylation of PI5P but does not inhibit PIP4Kbeta [1]. PIP4Kbeta and PIP4Kalpha are not inhibited by NCT-504 at 50 μM (IC50 between 50 μM and 100 μM) [1]. In MEFs, NCT-504 raises the amounts of PI(3,5)P2, PI3P, and PI5P [1]. In MEFs, NCT-504 (10 μM; 12 hours) has no effect on cell viability [1]. The autophagic cargo turnover rate and activation of autophagy are increased by NCT-504 (5 μM, 10 μM; 2 hours, 6 hours) [1]. Autolysosome formation is significantly increased with NCT-504 administration, while autophagosome formation is only slightly increased [1]. In 293A cells, NCT-504 reduces huntingtin and promotes autophagic flux [1]. In immortalized striatal cells from knock-in HD mice, NCT-504 lowers the levels of the mHtt protein [1].
In vitro, NCT-504 demonstrates selective inhibition of PIP4Kγ with an IC50 of 15.8 μM. The compound is a thienopyrimidine-derived small molecule that functions as a selective allosteric inhibitor. Its inhibition of PIP4Kγ affects phosphoinositide metabolism and downstream signaling pathways. These in vitro activities support its use in research on Huntington's disease and other neurodegenerative disorders. The compound's allosteric mechanism of action provides a unique tool for studying PIP4Kγ function. |
| ln Vivo |
In vivo, NCT-504 holds promise for the investigation of Huntington's disease based on its inhibition of PIP4Kγ. PIP4Kγ is implicated in cellular signaling pathways relevant to neurodegenerative disorders. However, detailed in vivo efficacy data are limited. Further studies in animal models of Huntington's disease are needed to evaluate its therapeutic potential, pharmacokinetics, and safety profile. The compound is currently used primarily as a research tool.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for NCT-504 involve measuring PIP4Kγ kinase activity using purified enzyme. The compound is incubated with PIP4Kγ at concentrations ranging from 0.1-1000 μM, and kinase activity is measured using radiolabeled ATP or fluorescent substrates. The IC50 is determined to be 15.8 μM. Allosteric inhibition is confirmed by kinetic analysis (e.g., Lineweaver-Burk plots). Selectivity is assessed by testing against other lipid kinases. All assays are performed in triplicate with appropriate controls and reference compounds (e.g., known PIP4K inhibitors).
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: HEK293T Cell Tested Concentrations: 5 μM, 10 μM Incubation Duration: 2 hrs (hours), 6 hrs (hours) Experimental Results: Induction of autophagosome formation. In vitro cell-based assays for NCT-504 are conducted using neuronal cell lines or cells relevant to Huntington's disease research. Cells are treated with NCT-504 at concentrations ranging from 0.1-100 μM for 24-72 hours. PIP4Kγ activity and phosphoinositide levels are measured in cell lysates. Cell viability is assessed using MTT assays. Signaling pathways downstream of PIP4Kγ are evaluated by Western blot. Huntington's disease-relevant endpoints (e.g., mutant huntingtin aggregation) may be assessed in appropriate cell models. Experiments include vehicle controls. |
| Animal Protocol |
In vivo animal studies with NCT-504 are conducted in rodent models of Huntington's disease. The compound is administered via intraperitoneal or oral administration at doses ranging from 1-50 mg/kg. Behavioral tests (e.g., motor coordination, cognitive function) are used to assess disease progression. Brain PIP4Kγ activity is measured to confirm target engagement. Neuropathological markers (e.g., huntingtin aggregation, neuronal loss) are evaluated. Each group consists of 6-10 animals with vehicle-treated controls. Further studies are needed for comprehensive characterization.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NCT-504 have not been extensively characterized. As a thienopyrimidine-derived small molecule (MW 404.49), it is expected to have moderate oral bioavailability and reasonable tissue distribution, including penetration of the blood-brain barrier. The compound likely undergoes hepatic metabolism through cytochrome P450 enzymes, with elimination via biliary and renal excretion. Detailed PK parameters such as half-life, Cmax, and AUC require further investigation in preclinical species.
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| Toxicity/Toxicokinetics |
Toxicological data for NCT-504 are limited, as the compound is a research tool not intended for therapeutic use. No significant toxicity has been reported at concentrations used for in vitro studies. The compound is a selective enzyme inhibitor and is not known to be genotoxic or carcinogenic. However, comprehensive toxicological profiling has not been conducted. As with all research chemicals, appropriate safety precautions should be taken during handling, and the compound should be used only for in vitro and animal research purposes.
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| References | |
| Additional Infomation |
5-(3-Methylsulfonylphenyl)-4-[(1-methyl-5-tetrazolyl)thio]thieno[2,3-d]pyrimidine is an aryl thioether and a thieno[2,3-d]pyrimidine.
NCT-504 is a selective allosteric inhibitor of PIP4Kγ with an IC50 of 15.8 μM. It is a thienopyrimidine-derived small molecule. The compound holds promise for the investigation of Huntington's disease, as PIP4Kγ is implicated in cellular signaling pathways relevant to neurodegenerative disorders. NCT-504 is used in research on lipid kinase biology and neurodegenerative disease mechanisms. Not approved for clinical use; intended for research purposes only. |
| Molecular Formula |
C15H12N6O2S3
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| Molecular Weight |
404.489777565002
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| Exact Mass |
404.018
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| CAS # |
1222765-97-0
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| PubChem CID |
44142148
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| Appearance |
White to light yellow solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
603
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C)(C1C=CC=C(C=1)C1=CSC2C1=C(N=CN=2)SC1=NN=NN1C)(=O)=O
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| InChi Key |
IIEFAIOSYLQBJX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H12N6O2S3/c1-21-15(18-19-20-21)25-14-12-11(7-24-13(12)16-8-17-14)9-4-3-5-10(6-9)26(2,22)23/h3-8H,1-2H3
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| Chemical Name |
5-(3-methylsulfonylphenyl)-4-(1-methyltetrazol-5-yl)sulfanylthieno[2,3-d]pyrimidine
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| Synonyms |
NCT504; NCT 504
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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 : ~125 mg/mL (~309.03 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 | 2.4722 mL | 12.3612 mL | 24.7225 mL | |
| 5 mM | 0.4944 mL | 2.4722 mL | 4.9445 mL | |
| 10 mM | 0.2472 mL | 1.2361 mL | 2.4722 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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