SM16, an orally active TGF-β type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model
SM16, an orally active TGF-β type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model
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DOI：
10.1161/atvbaha.107.158030
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发表时间：
2008-04-01
影响因子：
8.7
通讯作者：
Ling, Leona E.
中科院分区：
文献类型：
--
作者：
Fu, Kai;Corbley, Michael J.;Ling, Leona E.
目的：转化生长因子-β在血管损伤所致狭窄中起重要作用。本研究评价了一种新的Alk5/ALK4激酶小分子抑制剂在血管纤维化大鼠颈动脉损伤模型中的疗效。方法和结果-竞争结合分析和Biacore分析表明，小分子SM16与Alk5激酶ATP结合位点具有高亲和力。SM16可阻断转化生长因子-β和激活素诱导的Smad2/3磷酸化和转化生长因子-β诱导的纤溶酶原激活物抑制物(PAI)-荧光素酶活性。在一大批激酶检测中显示出良好的总体选择性，但SM16也显示出对ALK4的纳摩尔抑制和对Raf和p38的微弱(微摩尔)抑制。在大鼠颈动脉损伤模型上，SM16以15 mg/kg或30 mg/kg剂量连续给药14天后，可显著抑制新生内膜增厚和管腔狭窄。SM16还可阻止外膜平滑肌α-肌动蛋白阳性肌成纤维细胞的诱导和内膜胶原的产生，但不降低增殖细胞的百分比。结论-这些结果首次证明了口服活性小分子Alk5/ALK4抑制剂在血管纤维化模型中的有效性，并提示这些抑制剂在血管纤维化中的潜在治疗应用。
Objective - TGF-beta plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis.Methods and Results - The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-beta and activin-induced Smad2/3 phosphorylation and TGF-beta-induced plasminogen activator inhibitor (PAI)- luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak ( micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle alpha-actin-positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells.Conclusion - These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.