STATtic 是一种STAT3抑制剂。它选择性地抑制 STAT3 活化、二聚化和核转位。它抑制高亲和力磷酸肽与 STAT3 的 SH2 域结合。它可改善 Alport 综合征小鼠的肾功能不全。

Stattic is a small molecule inhibitor of STAT3. It selectively inhibits STAT3 activation, dimerization, and nuclear translocation (IC50: 5.1 μM).

Stattic inhibited binding of a phosphotyrosine-containing peptide derived from the gp130 receptor to the STAT3 SH2 domain in a strongly temperature-dependent manner: while only weak activity was observed at 22C, the compound displayed moderate activity at 30C and high potency at the physiologically relevant temperature of 37C (apparent IC50 value after 1 hr of incubation: 5.1 μM). Preincubation of serum-starved HepG2 cells with 20 μM of Stattic led to a selective reduction of phosphorylation of STAT3 Tyr705, while activation of STAT1 Tyr701 remained unchanged [1]. The viability of Ly3 cells grown in vitro was affected by Stattic in a dose-dependent manner and the anti-proliferative effect was associated with inhibition of STAT3 phosphorylation [2]. Stattic reduced the LPS-induced expression of ICAM-1 and VCAM-1 and STAT3 phosphorylation [3].

The anti-lymphoma activity of Stattic was observed in a Ly3 NOD-SCID IL2Rnull mouse model. The tumor growth inhibition was associated with decreased levels of phospho-STAT3 in all tumor samples isolated from Stattic treated mice compared to vehicle-treated mice [2].

The screening was performed at approximately 30C. The specificity of screening hits was validated in analogous assays for binding of the test compounds to the SH2 domains of STAT1, STAT5, and Lck. The final concentration of buffer components used for all FP assays was 10 mM HEPES (pH 7.5), 1 mM EDTA, 0.1% Nonidet P-40, 50 mM NaCl, and 10% DMSO. The absence of dithiothreitol is essential for inhibitory activity. The sequences of the peptides were: STAT3, 5-carboxyfluorescein-GY(PO3H2)LPQTV-NH2; STAT1, 5-carboxyfluorescein-GY(PO3H2)DKPHVL; STAT5, 5-carboxyfluorescein-GY (PO3H2)LVLDKW; and Lck, 5-carboxyfluorescein-GY(PO3H2)EEIP. Peptides were >95% pure. For specificity analysis at 30°C, proteins were used at 150 nM (STAT1, STAT3, and STAT5). For specificity analysis at 37°C, proteins were used at 370 nM (STAT3) or 100 nM (Lck). Proteins were incubated with test compounds in tubes at the indicated temperatures for 60 min prior addition of the respective 5-carboxyfluorescein labeled peptides (final concentration: 10 nM). Analysis of c-Myc/Max and Jun/Jun dimerization and DNA binding at 37°C was performed as described but in the absence of DTT. Before measurement at room temperature, the mixtures were allowed to equilibrate for at least 30 min. Test compounds were used at the indicated concentrations diluted from 20× stock in DMSO. Binding curves and inhibition curves were fitted with SigmaPlot. All competition curves were repeated three times in independent experiments. For the analysis of time dependence of the inhibition, the components were mixed from stock solutions kept at 0C and then incubated at 37C. Aliquots were taken at the indicated time points [1].

MDA-MB-231, MDA-MB-435S, and MDA-MB-453 cells were seeded. at 5 × 10^4 cells in 6-well plates, grown for 24 hr before adding DMSO or Stattic (final DMSO concentration 0.1%) and then incubated with the inhibitor for 24 hr. All cells were collected and resuspended in buffer (0.1% sodium citrate, 0.1% Triton X-100, 20 μM propidium iodide) and incubated for 3 hr before 10^4 cells per sample were analyzed by flow cytometry with a FACSCalibur equipped with a 488 nm laser [1].

19983-44-9

C8H5NO4S

211.19

STAT3 Inhibitor V

Ethanol:1.1 mg/mL (5 mM)
DMSO:10.6 mg/mL (50 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years