Design and Synthesis of Dual Galectin-3 and EGFR Inhibitors Against Liver Fibrosis,Chemistry - An Asian Journal

当前位置： X-MOL 学术 › Chem. Asian J. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Design and Synthesis of Dual Galectin-3 and EGFR Inhibitors Against Liver Fibrosis
Chemistry - An Asian Journal ( IF 3.5 ) Pub Date : 2024-11-06 , DOI: 10.1002/asia.202401078
Shuanglin Liu _{1,

2,

3} , Fei He _{4,

5} , Can Jin _{3,

4,

5} , Qing Li _{4,

5,

6} , Guilong Zhao _{3,

4,

5} , Kan Ding _{2,

3,

4,

5}

Affiliation

Liver fibrosis, mainly arising from chronic viral or metabolic liver diseases, is a significant global health concern. There is currently only one FDA-approved drug (Resmetirom) in the market to combat liver fibrosis. Both galectin-3 and epidermal growth factor receptor (EGFR) play important roles in liver fibrosis, while galectin-3 may interact with EGFR. Galectin-3 inhibitors, typically lactose or galactose derivatives may inhibit liver fibrosis. We hypothesized that targeting both galectin-3 and EGFR may have better effect against liver fibrosis. Here, EGFR inhibitor erlotinib was used in a series of designed galectin-3 inhibitors after hybridization with the pharmacophore structure in reported galectin-3 inhibitors to impede hepatic stellate cells (HSCs) activation by a typical method of click chemistry. Bioactivity test results showed that compound 29 suppressed TGF-β-induced upregulation of fibrotic markers (α-SMA, fibronectin-1, and collagen I). The preferred compound 29 displayed better binding to galectin-3 (K_D=52.29 μM) and EGFR protein (K_D=3.31 μM) by SPR assay. Further docking studies were performed to clarify the possible binding mode of compound 29 with galectin-3 and EGFR. Taken together, these results suggested that compound 29 could be a potential dual galectin-3 and EGFR inhibitor as leading compound for anti-liver fibrosis new drug development.

中文翻译：

设计和合成针对肝纤维化的双半乳糖凝集素-3 和 EGFR 抑制剂

肝纤维化主要由慢性病毒性或代谢性肝病引起，是一个重要的全球健康问题。目前市场上只有一种 FDA 批准的药物（Resmetirom）可用于对抗肝纤维化。半乳糖凝集素-3 和表皮生长因子受体（EGFR）在肝纤维化中起重要作用，而半乳糖凝集素-3 可能与 EGFR 相互作用。半乳糖凝集素-3 抑制剂，通常是乳糖或半乳糖衍生物，可抑制肝纤维化。我们假设同时靶向半乳糖凝集素-3 和 EGFR 可能对肝纤维化有更好的效果。在这里，EGFR 抑制剂厄洛替尼在与已报道的半乳糖凝集素-3 抑制剂中的药效团结构杂交后，被用于一系列设计的半乳糖凝集素-3 抑制剂，以通过典型的点击化学方法阻止肝星状细胞（HSC）活化。生物活性测试结果表明，化合物 29 抑制 TGF β诱导的纤维化标志物（α-SMA、纤连蛋白-1 和胶原蛋白 I）的上调。通过 SPR 测定，首选化合物 29 与半乳糖凝集素-3 （K_D=52.29 μM）和 EGFR 蛋白（K_D=3.31 μM）的结合效果更好。进行了进一步的对接研究，以阐明化合物 29 与半乳糖凝集素-3 和 EGFR 的可能结合模式。综上所述，这些结果表明，化合物 29 可能是一种潜在的半乳糖凝集素-3 和 EGFR 双重抑制剂，作为抗肝纤维化新药开发的主要化合物。

更新日期：2024-11-06

点击分享查看原文

点击收藏

阅读更多本刊新发论文