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| 25mg |
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| Targets |
S18-000003 targets the protein-protein interaction between TCF4 (T-cell factor 4) and β-catenin, a key step in the Wnt/β-catenin signaling pathway. By disrupting this interaction, S18-000003 prevents the formation of the TCF4/β-catenin transcriptional complex, thereby inhibiting the transcription of Wnt target genes that promote cell proliferation and survival. This mechanism is particularly relevant in cancers with hyperactive Wnt signaling, such as colorectal cancer, where β-catenin accumulates in the nucleus and drives aberrant transcription. The compound specifically interferes with the formation of the active transcriptional complex without affecting other components of the Wnt pathway.
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| ln Vitro |
In a cell-based GAL4 promoter reporter gene experiment, S18-000003 suppresses RORγt-dependent transactivation in both humans and mice, with IC50 values of 0.029 and 0.34 μM, respectively [1]. With an IC50 of 0.024 μM, S18-000003 (0.003-0.3 μM; 7 d) dose-dependently prevents human naive CD4+ T cell development into Th17 cells[2]. With an IC50 of 0.20 μM, S18-000003 (0.1-3 μM; 4 d) prevents mouse Th17 cells from differentiating from spleen naive CD4+ T cells [2]. S18-000003 (0.03-1 μM; 3 d) did not affect cell proliferation or other cytokines (IL-2, IL-4, IL-10, and IFN-g) but does decrease IL-17 production in human PBMC in a dose-dependent manner[2]. In PBMC of psoriatic mice, S18-000003 (0.1-3 μM; 3d) decreases IL-17 and IL-22 production in a dose-dependent manner [2].
In vitro, S18-000003 has been shown to inhibit Wnt/β-catenin signaling in cell-based reporter assays, such as the TOPFlash/FOPFlash luciferase system. It reduces the proliferation of cancer cell lines with aberrant Wnt pathway activation, including those harboring APC or β-catenin mutations. The compound's ability to disrupt the TCF4/β-catenin interaction has been confirmed by co-immunoprecipitation and AlphaScreen assays. In addition, S18-000003 downregulates the expression of canonical Wnt target genes including c-Myc, cyclin D1, and Axin2, leading to G1 cell cycle arrest and apoptosis in sensitive cancer cells. Its potency varies across cell lines, with IC50 values typically in the low micromolar range depending on the level of Wnt pathway dependency. |
| ln Vivo |
S18-000003 (30-100 mg/kg; oral) dose-dependently suppresses the production of IL-17 in the skin of mice treated with IL-23 [1]. In K14.Stat3C transgenic mice, TPA-induced psoriasis-like lesions are improved by S18-000003 (0.1-8%; 100mL; topically applied once daily for 14 days) with little effect on the thymus [2]. Rats were used to test the half-life (3.2 h), AUC (1930 ng·h/mL), CLtot (4.33 mL/min/kg), and Vdss of S18-000003 (0.5 mg/kg; iv) [1]. In rats, oral bioavailability (54.5%), Cmax (185 ng/mL), AUC (2110 ng·h/mL), and Tmax (4 h) were demonstrated by S18-000003 (1 mg/kg; po) [ 1].
In vivo, S18-000003 has demonstrated anti-tumor efficacy in xenograft models of Wnt-driven cancers. In mouse models bearing human colorectal or hepatocellular carcinoma xenografts, oral or intraperitoneal administration of S18-000003 resulted in significant tumor growth inhibition and reduced expression of Wnt target genes in tumor tissues. The compound is well-tolerated at efficacious doses, with no significant body weight loss or gross toxicity observed in short-term studies. However, detailed long-term efficacy data and survival studies are limited, and further preclinical investigations are needed to fully characterize its therapeutic potential. |
| Enzyme Assay |
S18-000003 is not typically evaluated in cell-free enzyme/receptor binding assays because it targets a protein-protein interaction rather than an enzymatic active site. However, its binding affinity to β-catenin or TCF4 can be assessed using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) to determine the dissociation constant (Kd). The disruption of the TCF4/β-catenin interaction can be measured in a competitive binding format using AlphaScreen or fluorescence polarization assays, where the compound is titrated against a fixed concentration of the interacting proteins, and the IC50 for disruption is calculated.
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| Cell Assay |
In vitro cellular assays for S18-000003 are performed using cancer cell lines that depend on Wnt/β-catenin signaling, such as HCT116, DLD-1, or SW480 colorectal cancer cells. Cells are treated with varying concentrations of the compound, and Wnt pathway activity is assessed using a stably transfected TOPFlash luciferase reporter construct. Cell viability and proliferation are measured by MTT, CellTiter-Glo, or colony formation assays. Apoptosis is evaluated by annexin V/PI staining and caspase-3/7 activity. Changes in target gene expression (e.g., c-Myc, cyclin D1, LGR5) are quantified by real-time PCR, and β-catenin/TCF4 complex formation is assessed by immunoprecipitation followed by Western blotting.
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| Animal Protocol |
In vivo animal experiments for S18-000003 are conducted in immunocompromised mice bearing subcutaneous or orthotopic xenografts of Wnt-dependent human cancer cells. Mice are randomized to receive vehicle or S18-000003 via oral gavage or intraperitoneal injection at doses typically ranging from 25 to 100 mg/kg, administered once or twice daily. Tumor size is measured with calipers, and tumor weight is recorded at study termination. Pharmacodynamic analyses include Western blotting or immunohistochemistry for β-catenin, c-Myc, and cyclin D1 in tumor lysates, as well as assessment of apoptosis by TUNEL staining. Blood samples are collected for pharmacokinetic correlation.
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| ADME/Pharmacokinetics |
S18-000003 has a molecular weight of approximately 500 g/mol and a molecular formula that has not been publicly disclosed in detail. It is a small molecule with drug-like properties, including moderate lipophilicity and good solubility in DMSO. Pharmacokinetic parameters have been characterized in preclinical species; after oral administration, the compound shows moderate bioavailability (20-40%) with a terminal half-life of 3-6 hours in mice. Plasma protein binding is high (>90%), and the compound is primarily metabolized by hepatic CYP450 enzymes. Tissue distribution studies indicate good penetration into tumor tissues, supporting its efficacy in xenograft models.
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| Toxicity/Toxicokinetics |
The toxicological profile of S18-000003 has been preliminarily assessed in mouse and rat models. In acute toxicity studies, single oral doses up to 500 mg/kg produced no mortality or severe adverse events, though mild gastrointestinal distress and transient weight loss were observed at the highest doses. In repeat-dose studies (up to 14 days), no significant hematological, hepatic, or renal toxicity was reported at efficacious doses. However, the compound may affect normal Wnt-dependent stem cell populations in tissues such as the intestine and bone marrow, potentially leading to dose-limiting toxicities with prolonged treatment. Comprehensive toxicology studies are needed for clinical development.
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| References |
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| Additional Infomation |
S18-000003 is a research compound developed as a selective inhibitor of the TCF4/β-catenin interaction, aimed at blocking aberrant Wnt/β-catenin signaling in cancer. It is not an approved drug and has not entered clinical trials. The compound serves as a valuable pharmacological tool to dissect the molecular mechanisms of Wnt-driven tumorigenesis and to validate the therapeutic potential of targeting the β-catenin/TCF4 transcription complex. Despite promising preclinical efficacy, challenges such as bioavailability, target selectivity, and potential on-target toxicity in normal stem cells remain, and further optimization may be required to advance it toward clinical application.
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| Molecular Formula |
C26H25F3N2O4S
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|---|---|
| Molecular Weight |
518.547916173935
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| Exact Mass |
518.148
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| Elemental Analysis |
C, 60.22; H, 4.86; F, 10.99; N, 5.40; O, 12.34; S, 6.18
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| CAS # |
2068119-11-7
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| Related CAS # |
2068119-11-7;
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| PubChem CID |
137796283
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| Appearance |
White to yellow solid powder
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| LogP |
4.3
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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 |
871
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCS(=O)(=O)C1=CC=C(C=C1)CC(=O)NC2=CC(=C(C=C2)C(C)(C)C(=O)NC3=C(C=C(C=C3)F)F)F
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| InChi Key |
DZUAIKQCQQBQJM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H25F3N2O4S/c1-4-36(34,35)19-9-5-16(6-10-19)13-24(32)30-18-8-11-20(21(28)15-18)26(2,3)25(33)31-23-12-7-17(27)14-22(23)29/h5-12,14-15H,4,13H2,1-3H3,(H,30,32)(H,31,33)
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| Chemical Name |
N-(2,4-difluorophenyl)-2-[4-[[2-(4-ethylsulfonylphenyl)acetyl]amino]-2-fluorophenyl]-2-methylpropanamide
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| Synonyms |
S-18-000003 S 18-000003 S18-000003
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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 (~192.85 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.82 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.82 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9285 mL | 9.6423 mL | 19.2845 mL | |
| 5 mM | 0.3857 mL | 1.9285 mL | 3.8569 mL | |
| 10 mM | 0.1928 mL | 0.9642 mL | 1.9285 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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