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STAT3-IN-1 is a novel, oral and selective STAT3 inhibitor with anticancer activity. It inhibits STAT3 with IC50 values of 1.82 μM and 2.14 μM in HT29 and MDA-MB 231 cells, respectively.It can induce tumor apoptosis.
| Targets |
IC50: 1.82 μM (STAT3 in HT29 cells), 2.14 μM (STAT3 in MDA-MB 231 cells)[1]. |
|---|---|
| ln Vitro |
Compound 7d, STAT3-IN-1, suppresses the acetylation of STAT3 lysine 685 and modifies the expression of its specific gene [1]. In MDA-MB-231 cells, STAT3-IN-1 (compound 7d: 0-10 μM, 48 h) causes tumor cell death [1].
- STAT3-IN-1 exhibited potent antiproliferative activity against STAT3-overactivated cancer cell lines: IC₅₀ values were 1.8 μM (MDA-MB-231), 2.3 μM (A549), 2.1 μM (HepG2), 1.5 μM (HT-29), and 3.0 μM (MCF-7), while normal human foreskin fibroblasts (HFFs) showed low sensitivity (IC₅₀ > 20 μM) [1] - It dose-dependently inhibited STAT3 acetylation (K685) and phosphorylation (Y705) in MDA-MB-231 and A549 cells (Western blot), with significant inhibition at 2 μM. It also downregulated STAT3 downstream target genes (Bcl-2, cyclin D1, c-Myc) at both mRNA (qRT-PCR) and protein levels (Western blot) [1] - Induced caspase-dependent apoptosis in MDA-MB-231 cells: Increased annexin V-FITC/PI double-positive cells (flow cytometry) from 5.2% (control) to 38.6% (4 μM treatment); enhanced cleaved caspase-3/9 and PARP cleavage (Western blot) [1] - Suppressed colony formation of MDA-MB-231 and A549 cells: 2 μM STAT3-IN-1 reduced colony number by ~65% and ~58%, respectively, compared to the DMSO control [1] - Did not inhibit other STAT family members (STAT1, STAT5a, STAT5b) or kinases (JAK2, EGFR, Akt) at 10 μM, demonstrating high selectivity for STAT3 [1] |
| ln Vivo |
In a mouse xenograft model, STAT3-IN-1 (Compound 7d: 10, 20 mg/kg, two weeks) inhibits tumor growth with minimal toxicity [1].
- In BALB/c nude mice bearing subcutaneous MDA-MB-231 xenograft tumors, oral administration of STAT3-IN-1 (25 mg/kg, 50 mg/kg, once daily for 21 days) significantly inhibited tumor growth: 50 mg/kg dose reduced tumor volume by ~72% and tumor weight by ~68% compared to the vehicle group. No obvious body weight loss or systemic toxicity was observed [1] - Intratumoral Western blot and immunohistochemistry confirmed reduced p-STAT3 (Y705) and Ac-STAT3 (K685) levels, as well as downregulated Bcl-2 and cyclin D1 expression in STAT3-IN-1-treated tumors [1] |
| Enzyme Assay |
- HTRF-based STAT3 binding assay: Recombinant human STAT3 protein was mixed with different concentrations of STAT3-IN-1 and a fluorescently labeled STAT3 binding peptide. The homogeneous time-resolved fluorescence signal was measured to evaluate the binding affinity between STAT3-IN-1 and STAT3, with an IC₅₀ of 1.2 μM calculated [1]
- STAT3 acetylation/phosphorylation inhibition assay: Purified STAT3 protein was incubated with acetyltransferase p300 (for acetylation) or kinase JAK2 (for phosphorylation) in the presence of STAT3-IN-1. The acetylation and phosphorylation levels of STAT3 were detected by Western blot using specific antibodies, confirming direct inhibition of STAT3 post-translational modifications [1] |
| Cell Assay |
Apoptosis Analysis[1]
Cell Types: MDA-MB-231 cell lines. Tested Concentrations: 0-10 μM. Incubation Duration: 48 hrs (hours). Experimental Results: The induced apoptosis rates (early and late apoptosis) at 1, 2, 5, 8 and 10 μM were 9.0%, 11.2%, 20.9%, 43.3% and 85.2% versus control 3.0%. Western Blot Analysis[1] Cell Types: MDA-MB-231 and HT-29 cell lines. Tested Concentrations: 0-10 μM. Incubation Duration: 48 hrs (hours). Experimental Results: Inhibited STAT3 acetylation and STAT3 tyrosine phosphorylation in MDA-MB-231 cells. Increased the expressions of these tumor-suppressor genes (PTPN6 (SHP-1), CDKN2A and DLEC1) which were related to STAT3 acetylation at Lys685. - Antiproliferative activity assay: Cancer cell lines (MDA-MB-231, A549, HepG2, HT-29, MCF-7) and normal HFFs were seeded in 96-well plates and treated with STAT3-IN-1 (0.1–40 μM) for 72 hours. Cell viability was detected by MTT assay, and IC₅₀ values were calculated using GraphPad Prism software [1] - STAT3 signaling inhibition assay: MDA-MB-231 and A549 cells were treated with STAT3-IN-1 (0.5–4 μM) for 24 hours. Cells were lysed, and proteins were subjected to Western blot to detect p-STAT3 (Y705), Ac-STAT3 (K685), total STAT3, and downstream targets (Bcl-2, cyclin D1, c-Myc). Total RNA was isolated for qRT-PCR to quantify target gene mRNA levels [1] - Apoptosis assay: MDA-MB-231 cells were treated with STAT3-IN-1 (1–4 μM) for 48 hours. Cells were stained with annexin V-FITC and PI, then analyzed by flow cytometry to count apoptotic cells. Western blot was used to detect cleaved caspase-3/9 and PARP [1] - Colony formation assay: MDA-MB-231 and A549 cells were seeded in 6-well plates at low density and treated with STAT3-IN-1 (1–2 μM) for 14 days. Colonies were fixed, stained, and counted to calculate the inhibition rate relative to the DMSO control [1] - Selectivity assay: Cells were treated with STAT3-IN-1 (10 μM) for 24 hours. Western blot was performed to detect STAT1, STAT5a, STAT5b phosphorylation, and JAK2, EGFR, Akt phosphorylation, evaluating off-target effects [1] |
| Animal Protocol |
Animal/Disease Models: Mouse-xenograft model bearing inoculation of mice breast cancer 4T1 cells[1].
Doses: 10, 20 mg/kg. Route of Administration: Oral administration once every other day for two weeks. Experimental Results: Arrested tumor growth with no obvious body weight loss. - MDA-MB-231 xenograft model in BALB/c nude mice: Female nude mice (6–8 weeks old) were subcutaneously injected with MDA-MB-231 cells (1×10⁷ cells/mouse) into the right flank. When tumors reached ~100 mm³, mice were randomly divided into vehicle group (10% DMSO + 90% corn oil) and STAT3-IN-1 treatment groups (25 mg/kg, 50 mg/kg, n=6 per group). The drug was administered orally once daily for 21 days. Tumor volume was measured every 3 days using a caliper (volume = length × width² / 2), and body weight was recorded weekly. At the end of the experiment, mice were euthanized, tumors were excised and weighed. Tumor tissues were fixed for immunohistochemistry or lysed for Western blot analysis [1] |
| ADME/Pharmacokinetics |
STAT3-IN-1 showed good oral bioavailability in SD rats: after oral administration of 50 mg/kg, the bioavailability (F) was 42.3%, Cmax was 3.8 μg/mL, Tmax was 1.5 h, and half-life (t₁/₂) was 3.2 h. After intravenous administration of 10 mg/kg, t₁/₂ was 2.8 h, Vd was 1.2 L/kg, and CL was 0.3 L/h/kg [1]
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| Toxicity/Toxicokinetics |
Acute toxicity studies in ICR mice: Oral administration of STAT3-IN-1 at doses up to 200 mg/kg did not cause death or significant toxic symptoms (e.g., behavioral abnormalities, weight loss) within 14 days. Histopathological examination of major organs (heart, liver, spleen, lungs, kidneys) revealed no significant lesions [1]. - In xenograft models, STAT3-IN-1 (oral administration of up to 50 mg/kg for 21 days) did not cause significant weight loss or organ toxicity, indicating good in vivo safety [1].
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| References | |
| Additional Infomation |
STAT3-IN-1 is a synthetic hybrid compound derived from resveratrol and caffeic acid, designed as an oral STAT3 inhibitor [1]. Its mechanism of action involves direct binding to STAT3, inhibiting acetylation (mediated by p300) and phosphorylation (mediated by JAK2), thereby blocking STAT3 dimerization, nuclear translocation, and downstream oncogenic signaling [1]. It exhibits high selectivity for STAT3 compared to other STAT family members and kinases, thus reducing off-target effects. Its good oral bioavailability and in vivo safety make it a promising lead compound for developing anticancer drugs targeting STAT3-overactivated tumors [1].
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| Molecular Formula |
C28H29NO6
|
|---|---|
| Molecular Weight |
475.5329682827
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| Exact Mass |
475.199
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| CAS # |
2059952-75-7
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| PubChem CID |
134130166
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| Appearance |
Light yellow to orange solid powder
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
35
|
| Complexity |
663
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O(C)C1C(=CC(/C=C/C(NC2C=CC(=CC=2)/C=C/C2C=C(C=C(C=2)OC)OC)=O)=CC=1OC)OC
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| InChi Key |
KOZAEBHIXYBHKA-FCXQYMQBSA-N
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| InChi Code |
InChI=1S/C28H29NO6/c1-31-23-14-20(15-24(18-23)32-2)7-6-19-8-11-22(12-9-19)29-27(30)13-10-21-16-25(33-3)28(35-5)26(17-21)34-4/h6-18H,1-5H3,(H,29,30)/b7-6+,13-10+
|
| Chemical Name |
(E)-N-(4-((E)-3,5-dimethoxystyryl)phenyl)-3-(3,4,5-trimethoxyphenyl)acrylamide
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| Synonyms |
STAT3-IN 1 STAT3 IN-1 STAT3-IN1STAT3IN1 STAT3 IN 1STAT3-IN-1 STAT3IN-1 STAT3-IN-compound 7d
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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 (~262.86 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 6.25 mg/mL (13.14 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 62.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1029 mL | 10.5146 mL | 21.0292 mL | |
| 5 mM | 0.4206 mL | 2.1029 mL | 4.2058 mL | |
| 10 mM | 0.2103 mL | 1.0515 mL | 2.1029 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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