PUBLICATION
Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis
- Authors
- Fu, C.W., Tsai, H.E., Chen, W.S., Chang, T.T., Chen, C.L., Hsiao, P.W., Li, W.S.
- ID
- ZDB-PUB-210101-1
- Date
- 2020
- Source
- Journal of medicinal chemistry 64(1): 527-542 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals, Genetically Modified
- Isoenzymes/antagonists & inhibitors*
- Humans
- Sialyltransferases/antagonists & inhibitors*
- Sialyltransferases/metabolism
- Integrins/metabolism
- Phosphorylation
- Focal Adhesion Protein-Tyrosine Kinases/metabolism
- Catalysis
- Zebrafish
- Signal Transduction/drug effects
- Cell Line, Tumor
- Female
- Breast Neoplasms/pathology*
- Neoplasm Metastasis/prevention & control*
- Talin/metabolism
- NF-kappa B/metabolism
- Animals
- Enzyme Inhibitors/pharmacology*
- Paxillin/metabolism
- Glycoproteins/metabolism
- Molecular Docking Simulation
- PubMed
- 33371679 Full text @ J. Med. Chem.
Citation
Fu, C.W., Tsai, H.E., Chen, W.S., Chang, T.T., Chen, C.L., Hsiao, P.W., Li, W.S. (2020) Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis. Journal of medicinal chemistry. 64(1):527-542.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping