Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown aetiology with limited treatment options. Currently, only two drugs, nintedanib and pirfenidone, are approved for the clinical treatment of IPF, but their efficacies are not satisfactory. Previous studies have shown that STAT3 might be a promising therapeutic target for IPF. Here, we designed several series of compounds and finally synthesized a total of 48 novel compounds as potential STAT3 inhibitors. Notably, compound 10K was the most promising compound with excellent inhibitory activity against STAT3 phosphorylation. Subsequently, the anti-pulmonary fibrosis effect of 10K was further investigated by TGF-β1-stimulated in vitro cell assay and bleomycin (BLM)-induced pulmonary fibrosis animal models. Specifically, compound 10K inhibited the TGF-β1 induced fibrotic response and blocked the epithelial-mesenchymal transition (EMT) of A549 cells, and its inhibitory effect was significantly better than that of Stattic. In addition, after oral administration of 10K, the symptoms of IPF in the lung tissue in the prevention and treatment mouse models were significantly reversed, and the efficacy was comparable to that of nintedanib. Moreover, 10K improved BLM-induced imbalance of immune microenvironment in lung tissue. Taken together, these results suggest that 10K could be a potential STAT3 inhibitor for the treatment of IPF.

特发性肺纤维化（IPF）是一种病因不明且治疗选择有限的慢性进行性肺部疾病。目前只有尼达尼布和吡非尼酮两种药物获批用于临床治疗IPF，但疗效并不理想。先前的研究表明 STAT3 可能是 IPF 的一个有前途的治疗靶点。在这里，我们设计了多个系列的化合物，最终合成了总共48个新化合物作为潜在的STAT3抑制剂。值得注意的是，化合物10K是最有前途的化合物，具有优异的 STAT3 磷酸化抑制活性。随后，通过TGF-β1刺激的体外细胞测定和博莱霉素（BLM）诱导的肺纤维化动物模型进一步研究了10K的抗肺纤维化作用。具体而言，化合物10K抑制TGF-β1诱导的纤维化反应，阻断A549细胞的上皮间质转化（EMT），其抑制效果明显优于Stattic。此外，口服10K后，防治小鼠模型肺组织IPF症状明显逆转，疗效与尼达尼布相当。此外，10K改善了 BLM 引起的肺组织免疫微环境失衡。综上所述，这些结果表明10K可能是治疗 IPF 的潜在 STAT3 抑制剂。