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| Targets |
NCGC00378430 targets the SIX1/EYA2 interaction, a transcriptional complex implicated in epithelial-mesenchymal transition (EMT) and metastatic progression. It acts as a small-molecule inhibitor of this protein-protein interaction. The compound reverses SIX1-induced TGF-β signaling and EMT.
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| ln Vitro |
NCGC00378430 exhibits an IC50 of 52 μM in the Alphascreen assay, making it a strong SIX1/EYA2 responder [1]. In T47D cells, NCGC00378430 (20 μM; 3 days) inhibits TGF-β-induced p-Smad3 activation, while NCGC00378430 (10 μM; 3 days) reverses the increase in p-SMAD3 caused by Sine ocuLis homeobox homolog 1 (SIX1), while leaving the overall E-CAD level unchanged. NCGC00378430 (10 or 20 μM) partially reverses SIX1-mediated regression in MCF7 breast tumor cells. NCGC00378430 (10 μM; for 3 days) impairs SIX1-EYA2 ligation in tumor cells (MCF7, T47D, MDA-MB-231 cells). Features[1].
In vitro, NCGC00378430 exhibits an IC50 of 52 μM in the Alphascreen assay. In T47D cells, NCGC00378430 (20 μM; 3 days) inhibits TGF-β-induced p-Smad3 activation. NCGC00378430 (10 μM; 3 days) reverses the increase in p-SMAD3 caused by SIX1 overexpression. NCGC00378430 (10 or 20 μM) partially reverses SIX1-mediated regression in MCF7 breast tumor cells. NCGC00378430 (10 μM; for 3 days) impairs SIX1-EYA2 ligation in tumor cells (MCF7, T47D, MDA-MB-231 cells). |
| ln Vivo |
NCGC00378430 (25 mg/kg; injected locally into the tumor site; daily; from day 3 to day 21) effectively lowers distant metastatic burden compared to commercial treatments [1]. NCGC00378430 (20 mg/kg; IV
In vivo, NCGC00378430 inhibits SIX1-mediated breast cancer metastasis in a mouse model. NCGC00378430 (25 mg/kg; injected locally into the tumor site; daily; from day 3 to day 21) effectively lowers distant metastatic burden compared to commercial treatments. |
| Enzyme Assay |
The in vitro binding assay for NCGC00378430 involves measuring the inhibition of the SIX1/EYA2 interaction. An Alphascreen assay is typically used, where a biotinylated SIX1 peptide and a His-tagged EYA2 protein are incubated in the presence of varying compound concentrations. The IC50 value (52 μM) is determined by quantifying the reduction in signal.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: T47D cells Tested Concentrations: 20 μM Incubation Duration: 3 days Experimental Results: Block TGF-β-induced p-Smad3 activation, FN1 upregulation and E-CAD downregulation. Cellular assays are performed using T47D, MCF7, and MDA-MB-231 cells. Cells are treated with NCGC00378430 at concentrations of 10 or 20 μM for 3 days. TGF-β signaling is assessed by measuring p-Smad3 activation by Western blotting. SIX1-EYA2 ligation is assessed by co-immunoprecipitation. |
| Animal Protocol |
Animal/Disease Models: Mouse[1]
Doses: 20 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)injection Experimental Results: T1/2α is 0.25 hrs (hrs (hours)), CL is 6.19 L/hr·kg, Vss is 4.08 L/ kg, Cmax is 6703 ng/mL, AUC is 3234 ng/mL·hr. In vivo animal studies are conducted in mouse models of breast cancer metastasis. NCGC00378430 is administered by local injection into the tumor site at 25 mg/kg daily from day 3 to day 21. Distant metastatic burden is assessed. |
| ADME/Pharmacokinetics |
NCGC00378430 has a molecular weight of 441.50 g/mol. In a pharmacokinetic study in mice (20 mg/kg; IV), the compound showed a T1/2α of 0.25 hrs, a CL of 6.19 L/hr·kg, a Vss of 4.08 L/kg, a Cmax of 6703 ng/mL, and an AUC of 3234 ng/mL·hr. It is soluble in DMSO at 88 mg/mL (199.32 mM).
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| Toxicity/Toxicokinetics |
Toxicity data for NCGC00378430 are not reported in the available sources. As a research compound, it is not intended for therapeutic use. Specific toxicological profiles have not been characterized.
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| References | |
| Additional Infomation |
NCGC00378430 is a research compound for studying SIX1/EYA2 function in cancer metastasis. It is a potent inhibitor of the SIX1/EYA2 protein-protein interaction. The compound is available from commercial suppliers for research use only.
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| Molecular Formula |
C22H23N3O5S
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| Molecular Weight |
441.50012421608
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| Exact Mass |
441.135
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| CAS # |
920650-00-6
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| PubChem CID |
16361161
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| Appearance |
White to off-white solid powder
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
700
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=C(N2C=CC=C2)C=CC=1)NC1C=C(S(N2CCOCC2)(=O)=O)C(OC)=CC=1
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| InChi Key |
IFXCVBOQNYHBMX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H23N3O5S/c1-29-20-8-7-18(16-21(20)31(27,28)25-11-13-30-14-12-25)23-22(26)17-5-4-6-19(15-17)24-9-2-3-10-24/h2-10,15-16H,11-14H2,1H3,(H,23,26)
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| Chemical Name |
N-(4-methoxy-3-morpholin-4-ylsulfonylphenyl)-3-pyrrol-1-ylbenzamide
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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 : ~100 mg/mL (~226.50 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.66 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 (5.66 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 | 2.2650 mL | 11.3250 mL | 22.6501 mL | |
| 5 mM | 0.4530 mL | 2.2650 mL | 4.5300 mL | |
| 10 mM | 0.2265 mL | 1.1325 mL | 2.2650 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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