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.
SIS3 HCl是一种Smad3抑制剂，可抑制Smad3 的磷酸化， IC50 为3 μM[1]。
SIS3 HCl可剂量依赖性地消除增强的p3TP-lux荧光素酶活性，减弱转化生长因子（TGF-1）诱导的Smad3磷酸化以及Smad3与Smad4的相互作用，但SIS3 HCl并不影响Smad2的磷酸化。SIS3 HCl通过减少转录活性来减轻TGF-1的作用，并通过TGF-1抑制成肌成纤维细胞的分化[1]。ML-12细胞中SIS3 HCl（10 μM）阻断了TGF-β介导的Smad3磷酸化，而总Smad2/3水平保持不变[2]。
在对Tie2-Cre；Loxp-EGFP小鼠的研究中，SIS3 HCl（2.5 mg/kg/day）可以抑制链脲佐菌素（STZ）诱导的糖尿病性肾病中Smad3的激活。SIS3 HCl可以消除内皮间质转化，减少肾脏纤维化，减缓肾病的进展[3]。SIS3 HCl（5mg/kg）能显著降低高脂饮食诱导的2型糖尿病（T2DM）模型小鼠的体重、脂肪量、空腹血糖，还能改善小鼠的胰岛素敏感性和口服葡萄糖耐量[4]。