生物活性

S31-201 inhibits the Stat3 transcription factor by blocking the phosphorylation and dimerization events necessary for activation. Selectively inhibits STAT3 DNA-binding activity in vitro (IC50 values are 86, 160, and >300 μM for STAT3-STAT3, STAT1-STAT3 and STAT1-STAT1 DNA-binding activity respectively). Blocks growth and induces apoptosis preferentially in tumor cells that contain persistently active STAT3 in vitro and arrests tumor growth in a murine xenograft model in vivo.

体外研究

体内研究

5% DMSO, 95% PEG 300

激酶实验

细胞实验

Cell line and culture conditions[1]

The LNCaP, IL‑6‑negative, cell line was cultured in Dulbecco's modified Eagle media supplementedwith 2 mM L‑glutamine, 10% heat‑inactivated fetal bovine serum, 100 U/ml penicillin G and 100 mg/mlstreptomycin and kept at 37˚C in a humidified incubator with an atmosphere of5% CO₂ and 95% air.

IC50determination and cell proliferation assay

The cells were seeded as 5x10³ cells per well in 200 μl complete culture medium containing variousconcentrations of IL‑6 (ranging between 1 and 100 ng/ml;recombinant human IL‑6), AG‑490(ranging between 1 and 100 μM), S3I‑201 (ranging between 1 and 300 μM) and TRAIL (rangingbetween 25 and 1,000 ng/ml). The cells were incubated for 24, 48 and 72 h,respectively, to determine cytotoxic and apoptotic effects. Cells treated with0.1% dimethyl sulfoxide served as a solvent control. Each concentration of IL‑6, AG490, S3I‑201 and TRAIL for each incubation periodwas repeatedly incubated in four wells to identify the most efficient dose(s)and incubation period(s). Viability IC50 values were identified as theconcentrations of the chemical agents causing 50% decrease in cell viability.Cytotoxic activity was measured using the water-soluble tetrazolium salt-1 (WST‑1) assay, following the manufacturer's instructions as previouslydescribed by Fortmüller et al (34). The spectrophotometrical absorbance of the sampleswas measured at 450 nm in a microplate enzyme‑linkedimmunosorbent assay (ELISA) reader. Experiments were conducted in triplicateand repeated at least three times. The IC50 was set as the values obtained whenAG490 and S3I‑201 concentrations were decreased to 50%of the control values. The absorbance values were normalized by assigning thevalue of the parent line in medium without drug to 1.0 and the value of the no‑cell control to 0. The most efficient incubation periods and dosesof IL‑6 and TRAIL were calculated for cell viability. The following IC50values were used for the LNCaP cell line: AG490, 50 μM; and S3I‑201, 300 μM.

动物实验

Mice and in Vivo Tumor Studies[2]

Six-week-old female athymic nude mice were maintained.Athymic nude mice were injected in the left flank area s.c. with 5x10⁶ human breast cancer MDA-MB-231 cells in 100 μl of PBS. After5–10 days, tumors with a diameter of 3 mm were established. Animals were givenS3I-201 i.v. at 5 mg/kg every 2 or 3 days for 2 weeks and monitored every 2 or3 days. Animals were stratified so that the mean tumor sizes in all treatmentwere nearly identical. Tumor volume was calculated according to the formula V =0.52x a² x b, where a is the smallest superficial diameter and b is the largestsuperficial diameter.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] Gurbuz V, Konac E, Varol N, et al. Effects of AG490 and S3I-201 on regulation of the JAK/STAT3 signaling pathway in relation to angiogenesis in TRAIL-resistant prostate cancer cells in vitro. Oncol Lett. 2014;7(3):755-763.
[2] Siddiquee K, Zhang S, Guida WC, et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A. 2007;104(18):7391-7396.

体内溶解度

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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