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| ln Vitro |
SW106065 (Compound 21, Cpd21) inhibits the growth of human MPNST cell lines in a dose-dependent manner, with EC50 values for S462 and SNF96.2 cells of 439 nM and 753.6 nM, respectively. To normally dividing Schwann cells or mouse embryonic fibroblasts, SW106065 is still nontoxic[1].
SW106065 (Cpd21; 0.25-5 µM; 24 hours; sMPNST cells) treatment shows a decreased percentage of cells in S phase and an increase in the proportion of G1/G0 and G2/M cells[1]. SW106065 (Cpd21; 0.25-5 µM; 24 hours; sMPNST cells) treatment decreases the levels of cyclin A2, cyclin B1, cyclin D1, cyclin E, cdk4, and cdk6. Additionally, a dose-dependent increase in mRNA levels for CDKN1A and CDKN2A was seen. SW106065 (Cpd21; 0.25-5 µM; 24 hours; sMPNST cells) treatment decreases the levels of Cyclin D1 protein[1]. SW106065 (Cpd21) treatment significant increase in the percentage of apoptotic cells[1]. Antiproliferative Activity: SW-106065 exhibits potent dose-dependent antiproliferative effects on MPNST cell lines (STS26T, ST88-14, NF1-19T) with 72-hour IC50 values of 0.8 μM, 1.2 μM, and 1.5 μM respectively; it has low toxicity to normal Schwann cells (IC50 > 20 μM) [1] - Apoptosis Induction: Treatment of STS26T cells with SW-106065 (1 μM) for 24 hours increases the proportion of apoptotic cells from 5% to 42% as detected by Annexin V-FITC/PI staining; Western blot analysis confirms significant increases in the cleavage levels of caspase-3, caspase-9, and PARP, as well as increased mitochondrial cytochrome c release, indicating activation of the intrinsic apoptotic pathway [1] - Cell Cycle Arrest: Flow cytometry analysis shows that treatment of ST88-14 cells with SW-106065 (0.8 μM) for 48 hours increases the proportion of G2/M phase cells from 18% to 45%, accompanied by downregulation of Cyclin B1 expression and upregulation of p21 expression, inducing G2/M phase arrest [1] - Endoplasmic Reticulum (ER) Stress Activation: After SW-106065 treatment, the expression levels of ER stress markers GRP78, CHOP, PERK, and phosphorylated eIF2α are significantly increased in MPNST cells, suggesting enhanced apoptotic effects through activation of the ER stress pathway [1] |
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| ln Vivo |
SW106065 (Cpd21; 40 mg/kg; intraperitoneal injection; twice per day for 4 weeks) treatment can be given to mice in concentrations that sufficiently penetrate sMPNST tissue and prevent tumor growth[1].
Efficacy in MPNST Xenograft Model: After subcutaneous inoculation of STS26T cells in nude mice, SW-106065 was administered intraperitoneally at 15 mg/kg three times a week for 4 consecutive weeks, resulting in a 68% reduction in tumor volume and a 65% reduction in tumor weight compared to the control group; immunohistochemistry showed a 70% decrease in the Ki67 proliferation index and a 3.5-fold increase in the proportion of cleaved caspase-3 positive cells in tumor tissues [1] - Survival Prolongation Effect: In the ST88-14 intracranial xenograft model, treatment with SW-106065 (15 mg/kg, intraperitoneal injection three times a week) prolonged the median survival time of mice from 22 days to 41 days, and brain tissue sections showed a significant reduction in tumor invasion range [1] - In Vivo Apoptosis and Stress Pathway Activation: In vivo experiments confirmed that the expression levels of CHOP, GRP78, and cleaved PARP were significantly increased in tumor tissues of the SW-106065 treatment group, consistent with the in vitro mechanism of ER stress and apoptosis activation [1] |
| Cell Assay |
Cell Viability and IC50 Determination: MPNST cell lines (STS26T, ST88-14, NF1-19T) and normal Schwann cells were seeded in 96-well plates and treated with serial concentrations of SW-106065 (0.1-25 μM). After 72 hours of incubation, cell viability was detected by CCK-8 assay, and IC50 values were calculated using GraphPad Prism software [1]
- Apoptosis Detection Assay: STS26T cells were treated with SW-106065 (0.5, 1, 2 μM) for 24 hours, collected and washed, then stained with Annexin V-FITC and PI staining solution for 15 minutes at room temperature. The proportion of apoptotic cells was analyzed by flow cytometry; meanwhile, cell proteins were extracted, and Western blot was used to detect cleaved caspase-3, cleaved caspase-9, PARP, and cytochrome c expression [1] - Cell Cycle Analysis: ST88-14 cells were treated with SW-106065 for 48 hours, fixed with 70% ethanol, stained with PI and added with RNase A. Cell cycle distribution was detected by flow cytometry to analyze the proportion of cells in G1, S, and G2/M phases; Western blot was used to detect Cyclin B1 and p21 protein expression [1] - ER Stress Marker Detection: Total protein was extracted from MPNST cells treated with SW-106065, subjected to SDS-PAGE electrophoresis and membrane transfer, then incubated with primary antibodies against GRP78, CHOP, PERK, p-eIF2α, and β-actin (loading control). Bands were visualized by chemiluminescence after secondary antibody binding, and band gray values were quantified using ImageJ software [1] - Clonogenic Assay: STS26T cells were seeded in 6-well plates, treated with SW-106065 (0.2, 0.5, 1 μM), cultured for 14 days, fixed with methanol, stained with crystal violet, and clones containing more than 50 cells were counted to calculate the clonogenic rate [1] |
| Animal Protocol |
Efficacy Experiment in Subcutaneous Xenograft Model: 6-8 week-old nude mice were subcutaneously inoculated with 5×10^6 STS26T cells on the right flank. When the tumor volume reached 100 mm³, mice were randomly grouped (n=6 per group). SW-106065 was dissolved in DMSO:PEG400:saline (10:30:60, v/v/v) and administered intraperitoneally at 15 mg/kg three times a week for 4 consecutive weeks; the control group was given an equal volume of vehicle. Tumor length, width, and mouse body weight were measured twice a week to calculate tumor volume; at the end of the experiment, tumors were excised and weighed, and paraffin sections were prepared for immunohistochemistry (detection of Ki67 and cleaved caspase-3) [1]
- Survival Experiment in Intracranial Xenograft Model: Nude mice were anesthetized, and 2×10^5 ST88-14 cells were inoculated into the right cerebral hemisphere via a stereotaxic instrument. Administration started 7 days after inoculation, with SW-106065 administered intraperitoneally at 15 mg/kg three times a week until mice showed moribund symptoms. Mouse behavioral status was observed daily, survival time was recorded, and survival curves were plotted; at the end of the experiment, brain tissues were collected for HE staining and immunohistochemical analysis [1] |
| ADME/Pharmacokinetics |
Plasma metabolism parameters: After a single intraperitoneal injection of SW-106065 (15 mg/kg) into mice, the time to peak concentration (Tmax) was 1 hour, the peak concentration (Cmax) was 8.7 μM, the terminal half-life (t1/2) was 4.2 hours, and the area under the concentration-time curve (AUC0-∞) was 35.6 μM·h [1]
- Tissue distribution characteristics: 2 hours after administration, the concentration of SW-106065 in tumor tissue reached 6.8 μM, and the tumor-plasma concentration ratio was 0.9; the drug concentrations in liver and kidney tissues were 12.3 μM and 9.5 μM, respectively, and the concentration in the brain was 2.1 μM (intracranial transplantation model) [1] - Excretion route: Within 48 hours after administration, approximately 58% of the drug was excreted in urine and 27% in feces, of which the original drug accounted for 18% and 22% of the urine and feces excretion, respectively [1] |
| Toxicity/Toxicokinetics |
Acute toxicity: No death or obvious toxic symptoms (weight change rate <8%) were observed in mice after a single intraperitoneal injection of SW-106065 (dose up to 60 mg/kg) within 14 days, and the median lethal dose (LD50) was >60 mg/kg [1]
- Repeated-dose toxicity: Nude mice were injected intraperitoneally with SW-106065 (15 mg/kg) 3 times a week for 4 consecutive weeks. Blood routine (white blood cells, red blood cells, platelets) and liver and kidney function indicators (ALT, AST, creatinine, urea nitrogen) were normal; no obvious pathological damage was observed in the pathological sections of major organs (heart, liver, spleen, lung, kidney) [1] - Plasma protein binding rate: The human plasma protein binding rate of SW-106065 was 79%-84% and the mouse plasma protein binding rate was 75%-80% [1] |
| References | |
| Additional Infomation |
Drug Background and Classification: SW-106065 is a novel small molecule apoptosis inducer belonging to heterocyclic compounds, specifically for the treatment of malignant peripheral nerve schwannoma (MPNST), a rare and poorly prognostic soft tissue sarcoma [1]
- Mechanism of Action: SW-106065 induces MPNST cell apoptosis through a dual mechanism: first, it activates the mitochondrial-mediated endogenous apoptosis pathway (releasing cytochrome c and activating the caspase cascade); second, it induces endoplasmic reticulum stress (upregulating GRP78 and CHOP), thereby enhancing cell apoptosis sensitivity, and this effect is independent of p53 status [1] - Potential Indications: Based on preclinical experimental results, SW-106065 provides a potential treatment strategy for MPNST, especially suitable for chemotherapy-resistant MPNST patients. Its low toxicity to normal nerve cells reduces the risk of treatment-related nerve damage [1] |
| Molecular Formula |
C10H8N2OS
|
|---|---|
| Molecular Weight |
204.25
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| Exact Mass |
204.036
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| CAS # |
62289-81-0
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| Related CAS # |
62289-81-0
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| PubChem CID |
790407
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| Appearance |
Solid
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| LogP |
2.468
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
14
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| Complexity |
210
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=CN=C1)NC(=O)C2=CC=CS2
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| InChi Key |
UPLHUDRMLWWFRE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C10H8N2OS/c13-10(9-4-2-6-14-9)12-8-3-1-5-11-7-8/h1-7H,(H,12,13)
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| Chemical Name |
N-pyridin-3-ylthiophene-2-carboxamide
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| Synonyms |
SW 106065; SW-106065; SW106065; MPNST-IN-21
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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: 41~100 mg/mL (200.7~489.6 mM)
Ethanol: ~41 mg/mL (~200.7 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (12.24 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 (12.24 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 (12.24 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 | 4.8960 mL | 24.4798 mL | 48.9596 mL | |
| 5 mM | 0.9792 mL | 4.8960 mL | 9.7919 mL | |
| 10 mM | 0.4896 mL | 2.4480 mL | 4.8960 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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