Stattic (Synonyms: STAT3 Inhibitor V)

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].

References:
[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.