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Design and Synthesis of Dual Galectin-3 and EGFR Inhibitors Against Liver Fibrosis
Shuanglin Liu1,2,3, Fei He4,5, Can Jin3,4,5
1School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, China.
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.
Insights
Researchers developed a novel compound, compound 29, that targets both galectin-3 and epidermal growth factor receptor (EGFR) to combat liver fibrosis. This dual-action inhibitor shows promise for new anti-liver fibrosis drug development.
Area of Science:
- Medicinal Chemistry
- Hepatology
- Drug Discovery
Background:
- Liver fibrosis is a major health issue driven by chronic liver diseases, with limited treatment options.
- Galectin-3 and epidermal growth factor receptor (EGFR) are key players in liver fibrosis progression.
- Existing galectin-3 inhibitors offer potential, but dual-targeting strategies may enhance efficacy.
Purpose of the Study:
- To design and synthesize novel compounds targeting both galectin-3 and EGFR for potential anti-liver fibrosis therapy.
- To evaluate the efficacy of these compounds in inhibiting hepatic stellate cell activation and fibrotic markers.
- To identify a lead compound for further preclinical development.
Main Methods:
- Hybridization of EGFR inhibitor erlotinib with galectin-3 inhibitor pharmacophores.
- Synthesis of novel compounds using click chemistry.
- Bioactivity assays to assess inhibition of fibrotic markers (α-SMA, fibronectin-1, collagen I) in TGF-β-induced models.
- Surface Plasmon Resonance (SPR) assay to determine binding affinity to galectin-3 and EGFR.
- Molecular docking studies to elucidate binding modes.
Main Results:
- Compound 29 effectively suppressed TGF-β-induced upregulation of key fibrotic markers.
- Compound 29 demonstrated significant binding affinity to both galectin-3 (KD=52.29 μM) and EGFR (KD=3.31 μM).
- Docking studies provided insights into the binding interactions of compound 29 with target proteins.
Conclusions:
- Compound 29 acts as a potent dual inhibitor of galectin-3 and EGFR.
- This novel compound represents a promising lead for the development of new anti-liver fibrosis drugs.
- Targeting both galectin-3 and EGFR simultaneously offers a potential therapeutic strategy for liver fibrosis.
