Stattic is the first non-peptide small molecule inhibitor of STAT3, which effectively inhibits STAT3 activation and nuclear translocation. Its IC50 is 5.1 μM, and its selectivity on STAT3 is much higher than that on STAT1[1].Stattic inhibits the binding of a high affinity phosphopeptide for the SH2 domain of STAT3[2].
The viability of Ly3 cells cultured in vitro was affected by two inhibitors(STATTIC and S31-201) tested in a dose-dependent manner, and the antiproliferative effect was associated with inhibition of STAT3 phosphorylation[3]. Stattic directly or indirectly reduces histone acetylation and suggest reevaluation of Stattic and related compounds as polypharmacological agents through multipronged cytotoxic effects on cancer cells[5]. Exposure of dendritic cells (DCs) to conditioned media (CM) from cancer cells treated with stattic and/or DOX resulted in secretion of IL-12, which is an indicator of DCs maturation and induction of Th1 response[7].
The effects of both inhibitors(STATTIC and S31-201) were tested in a dose-dependent manner, and the antiproliferative effects were associated with the inhibition of STAT3 phosphorylation. The antilymphoma activity of STATTIC was also observed in the Ly3 NOD/SCID IL2Rnull mouse model, and the inhibition of tumor growth was significant[3].In AC mice, Phosphorylated STAT3 was upregulated in AS kidneys and glomeruli. Treatment with stattic ameliorated the progressive renal dysfunction, such as increased levels of proteinuria, BUN and serum creatinine. Stattic also significantly suppressed the gene expression levels of renal injury markers (Lcn2, Kim-1), pro-inflammatory cytokines (Il-6, KC), pro-fibrotic genes (Tgf-β, Col1a1, α-Sma) and Mmp9. Stattic treatment decreased the renal fibrosis congruently with the decrease of transforming growth factor beta (TGF-β) protein and increase of antifibrosis-associated markers p-Smad1, 5 and 8, which are negative regulators of TGF-β signaling[4]. To investigate the effects of STAT3 here, LPS/d-GalN-induced hepatic damage was induced in mice, the STAT3 inhibitor Stattic was administered, and the degree of liver injury, inflammation, and hepatocyte apoptosis were investigated[6].
参考文献:
[1]: Lin L, Jou D, et,al. STAT3 as a potential therapeutic target in ALDH+ and CD44+/CD24+ stem cell-like pancreatic cancer cells. Int J Oncol. 2016 Dec;49(6):2265-2274. doi: 10.3892/ijo.2016.3728. Epub 2016 Oct 12. PMID: 27748818; PMCID: PMC5118001.
[2]: McMurray JS. A new small-molecule Stat3 inhibitor. Chem Biol. 2006 Nov;13(11):1123-4. doi: 10.1016/j.chembiol.2006.11.001. PMID: 17113993.
[3]: Scuto A, Kujawski M, et,al.STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma. Cancer Res. 2011 May 1;71(9):3182-8. doi: 10.1158/0008-5472.CAN-10-2380. Epub 2011 Apr 26. PMID: 21521803; PMCID: PMC3085657.
[4]: Yokota T, Omachi K, et,al. STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model. Nephrol Dial Transplant. 2018 Feb 1;33(2):214-223. doi: 10.1093/ndt/gfx246. PMID: 28992339.
[5]: Poria DK, Sheshadri N, et,al. The STAT3 inhibitor Stattic acts independently of STAT3 to decrease histone acetylation and modulate gene expression. J Biol Chem. 2021 Jan-Jun;296:100220. doi: 10.1074/jbc.RA120.016645. Epub 2020 Dec 25. PMID: 33839684; PMCID: PMC7948742.
[6]: Li S, Hu K, et,al. Stattic alleviates acute hepatic damage induced by LPS/d-galactosamine in mice. Innate Immun. 2021 Feb;27(2):201-209. doi: 10.1177/1753425920988330. PMID: 33576722; PMCID: PMC7882804.
[7]: Jafari S, Lavasanifar A, et,al. STAT3 inhibitory stattic enhances immunogenic cell death induced by chemotherapy in cancer cells. Daru. 2020 Jun;28(1):159-169. doi: 10.1007/s40199-020-00326-z. Epub 2020 Jan 16. PMID: 31942696; PMCID: PMC7214602.
Stattic是第一个非肽类小分子STAT3抑制剂，能有效抑制STAT3的激活和核转位。其IC50为5.1 μM，对STAT3的选择性远高于对STAT1[1]。Stattic抑制一种高亲和力的磷酸肽与STAT3的SH2结构域的结合[ 2].
两种抑制剂（STATTIC和S31-201）体外培养的Ly3细胞活力受剂量依赖性影响，抗增殖作用与抑制相关STAT3 磷酸化[3]。 Stattic 直接或间接降低组蛋白乙酰化，并建议通过对癌细胞的多管齐下的细胞毒作用重新评估 Stattic 和相关化合物作为多药理学药物[5]。树突状细胞 (DC) 暴露于经静态和/或 DOX 处理的癌细胞的条件培养基 (CM) 会导致分泌 IL-12，这是 DC 成熟和诱导 Th1 反应的指标[7].
两种抑制剂（STATTIC 和 S31-201）的作用均呈剂量依赖性，抗增殖作用与抑制 STAT3 磷酸化有关。在 Ly3 NOD/SCID IL2Rnull 小鼠模型中也观察到 STATTIC 的抗淋巴瘤活性，对肿瘤生长的抑制作用显着[3]。在 AC 小鼠中，磷酸化的 STAT3 在 AS 肾脏和肾小球中上调. stattic 治疗改善了进行性肾功能障碍，例如蛋白尿、BUN 和血清肌酐水平升高。 Stattic 还显着抑制肾损伤标志物 (Lcn2、Kim-1)、促炎细胞因子 (Il-6、KC)、促纤维化基因 (Tgf-β, Col1a1, α-Sma) 和Mmp9。静态治疗与转化生长因子 β (TGF-β) 蛋白的减少和抗纤维化相关标志物 p-Smad1、5 和 8 的增加一致地降低了肾纤维化，它们是 TGF-β 的负调节因子；信号[4]。为了研究 STAT3 的作用，在小鼠中诱导了 LPS/d-GalN 诱导的肝损伤，给予 STAT3 抑制剂 Stattic，并研究了肝损伤、炎症和肝细胞凋亡的程度[6].
| Kinase experiment [1]: | |
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Preparation Method |
Screening was performed at approximately 30 °C to verify the specificity of the screening by similar experiments in which the experimental compounds( Stattic ) were bound to the SH2 domains of STAT1, STAT5, and Lck |
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Reaction Conditions |
Stattic and protein for 60min |
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Applications |
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 22°C, the compound displayed moderate activity at 30°C and high potency at the physiologically relevant temperature of 37°C (apparent IC50 value after 1 hr of incubation: 5.1 ± 0.8 μM). |
| Cell experiment [2]: | |
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Cell lines |
Ly3 cells |
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Preparation Method |
Ly3 parental cells were plated in the presence of 10% FBS and treated with Stattic at indicated concentrations for 24 or 48 h. Phosphorylated STAT3 levels or cell proliferation were analyzed by flow cytometry or MTS assays, respectively. |
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Reaction Conditions |
1/2.5uM Stattic for 24 or 48 h |
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Applications |
The viability of Ly3 cells cultured in vitro was affected by two inhibitors(STATTIC and S31-201) tested in a dose-dependent manner, and the antiproliferative effect was associated with inhibition of STAT3 phosphorylation. |
| Animal experiment [3]: | |
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Animal models |
4-6-week-old athymic nude mice |
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Preparation Method |
Ly3 parental tumor-bearing mice were treated daily with vehicle or STATTIC at 3.75mg/kg. Two hours after the last treatment, samples were collected from each group to prepare whole-cell lysates and Western blotting analysis was performed to detect phosphorylated STAT3 levels |
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Dosage form |
3.75mg/kg STATTIC for 8 days |
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Applications |
The effects of both inhibitors were tested in a dose-dependent manner, and the antiproliferative effects were associated with the inhibition of STAT3 phosphorylation. The antilymphoma activity of STATTIC was also observed in the Ly3 NOD/SCID IL2Rnull mouse model, and the inhibition of tumor growth was significant. |
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参考文献: [1]. Schust J, Sperl B, et,al. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006 Nov;13(11):1235-42. doi: 10.1016/j.chembiol.2006.09.018. PMID: 17114005. [2]. Scuto A, Kujawski M, et,al.STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma. Cancer Res. 2011 May 1;71(9):3182-8. doi: 10.1158/0008-5472.CAN-10-2380. Epub 2011 Apr 26. PMID: 21521803; PMCID: PMC3085657. |
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