小分子药物sorafenib类似物在器官纤维化疾病进程中的效用及其分子机制研究

As a non-physiological wound healing in multiple organs, fibrosis represents the final common pathway of many chronic diseases and becomes a major determinant of morbidity and mortality worldwide. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that epithelial-mesenchymal transition (EMT) is a key step for fibrogenesis, in which transforming growth factor-β (TGF-β) is a pivotal inducer. Thus, a number of therapeutic interventions that interfere with TGF-β signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we identified sorafenib as a novel inhibitor that counteracted the profibrotic activity of TGF-β signaling and thereby improved hepatic and pulmonary fibrosis in mice. In this project, we will design a number of sorafenib analogues and evaluate their effects on EMT, myofibroblast activation and organ fibrosis both in vitro and in vivo. Additionally, we will explore the underlying molecular mechanism of sorafenib analogues and provide a potential interpretation for their antifibrotic effects. Certainly, these studies will shed light on the therapeutic translation of sorafenib and its analogues for the clinical treatments of fibrotic diseases.

人体重要脏器纤维化发病率高、危害性大、缺乏有效治疗方法。上皮-间质转化（EMT)在纤维化疾病的发生和发展中起重要作用，而TGF-β是最关键的诱导因子。在之前的研究中，我们筛选发现多个干扰TGF-β信号的化合物。其中，sorafenib显著抑制TGF-β信号、EMT和肌成纤维细胞活化，并能有效改善小鼠肝、肺纤维化症状。sorafenib作为多靶点的小分子激酶抑制剂，存在很大的毒副作用。为了寻找有效、低毒的抗纤维化药物，我们设计、合成了多个sorafenib类似物。这些化合物在器官纤维化疾病进程中发挥什么功能？其分子机制是什么？都是尚待解决的科学问题。在本项目中，我们将研究sorafenib类似物对EMT和成纤维细胞活化的影响，并在肝、肺纤维化小鼠模型上开展药效评估，同时从sorafenib新靶点5-HT2B受体入手，研究这些化合物改善纤维化的分子机制，为研发抗纤维化新药物提供理论和实验基础。

人体重要脏器纤维化发病率高、危害性大、缺乏有效治疗方法。上皮-间质细胞转换（EMT)在器官纤维化疾病的发生和发展中起到重要作用，而TGF-β信号是最关键的诱导因子。在之前的研究中，我们筛选发现小分子药物sorafenib显著抑制TGF-b信号和EMT，并能有效改善小鼠肝、肺纤维化症状。由于sorafenib是多靶点的小分子激酶抑制剂，存在很大的毒副作用。为了寻找有效、低毒的抗纤维化药物，我们在本项目中设计、合成了多个sorafenib类似物，筛选发现TCC能够显著抑制TGF-β信号和EMT，并在肝纤维化动物模型上进行药效评估。同时，我们还从sorafenib新靶点5-HT2B受体入手，研究5-HT2B受体拮抗剂对包括纤维化等疾病的效用及其可能的分子机制。这些结果将为今后进一步开发高效、低毒的抗纤维化新药物提供理论和研究基础。