SIS3 HCl is a Smad3 inhibitor that inhibits the phosphorylation of Smad3 with an IC50 of 3 μM [1].
SIS3 HCl can dose-dependently eliminate enhanced p3TP-lux luciferase activity, attenuated Smad3 phosphorylation induced by transforming growth factor (TGF-1) and the interaction between Smad3 and Smad4, but SIS3 HCl does not affect Smad2 phosphorylation. SIS3 HCl attenuates the effects of TGF-1 by reducing transcriptional activity and inhibits differentiation of adult myofibroblasts via TGF-1[1]. SIS3 HCl (10 μM) in ML-12 cells blocked TGF-β-mediated Smad3 phosphorylation, while total Smad2/3 levels remained unchanged[2].
In a study of Tie2-Cre; Loxp-EGFP mice, SIS3 HCl (2.5 mg/kg/day) inhibited Smad3 activation in streptozotocin (STZ)-induced diabetic nephropathy. SIS3 HCl eliminates endothelial mesenchymal transition, reduces renal fibrosis, and slows the progression of kidney disease[3]. SIS3 HCl (5 mg/kg) significantly reduced body weight, adiposity, and fasting blood glucose in high-fat diet-induced type 2 diabetes mellitus (T2DM) model mice, and also improved insulin sensitivity and oral glucose tolerance in mice[4].
References:
[1] Jinnin M et al. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol. 2006 Feb;69(2):597-607.
[2] Leiting S, Seidl S, Martinez-Palacian A, Muhl L, Kanse SM. Transforming Growth Factor-β (TGF-β) Inhibits the Expression of Factor VII-activating Protease (FSAP) in Hepatocytes. J Biol Chem. 2016 Sep 30;291(40):21020-21028.
[3] Li J et al. Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. Diabetes.2010 Oct;59(10):2612-24.
[4] Wang D C, Yan T T, Chen B, et al. SIS3, a good candidate for the reverse of type 2 diabetes mellitus in mice[J]. Fundamental & Clinical Pharmacology, 2021, 35(2): 389-396.