2. Academic Validation
  3. Design and Synthesis of Dual Galectin-3 and EGFR Inhibitors Against Liver Fibrosis

Design and Synthesis of Dual Galectin-3 and EGFR Inhibitors Against Liver Fibrosis

  • Chem Asian J. 2025 Jan 17;20(2):e202401078. 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
Affiliations

Affiliations

  • 1 School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, China.
  • 2 Henan Polysaccharide Research Center, Henan Key Laboratory of Chinese Medicine for Polysaccharides and Drugs Research, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
  • 3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan, Guangdong, Tsuihang New District, 528400, China.
  • 4 Glycochemistry and Glycobiology Lab, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 5 University of Chinese Academy of Science, No.19 A Yuquan Road, Beijing, 100049, China.
  • 6 School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China.
PMID: 39504308 DOI: 10.1002/asia.202401078
Abstract

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 (KD=52.29 μM) and EGFR protein (KD=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.

Keywords

EGFR; Galectin-3; Inhibitor; Liver fibrosis; Synthesis.

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