Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis.

Abstract

We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.

• Authors: Chih-Wei Fu, Han-En Tsai, Wei-Sheng Chen, Tzu-Ting Chang, Chia-Ling Chen, Pei-Wen Hsiao, Wen-Shan Li
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 1 Pg. 527-542 (01 14 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33371679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Glycoproteins
• Integrins
• Isoenzymes
• NF-kappa B
• PXN protein, human
• Paxillin
• Talin
• Sialyltransferases
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Animals
• Animals, Genetically Modified
• Breast Neoplasms (pathology)
• Catalysis
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Female
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Glycoproteins (metabolism)
• Humans
• Integrins (metabolism)
• Isoenzymes (antagonists & inhibitors)
• Molecular Docking Simulation
• NF-kappa B (metabolism)
• Neoplasm Metastasis (prevention & control)
• Paxillin (metabolism)
• Phosphorylation
• Sialyltransferases (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Talin (metabolism)
• Zebrafish