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Development of a FUT8 Inhibitor with Cellular Inhibitory Properties
Yoshiyuki Manabe1,2, Tomoyuki Takebe1, Satomi Kasahara1
1Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.
Abstract:
Core fucosylation is catalyzed by α-1,6-fucosyltransferase (FUT8), which fucosylates the innermost GlcNAc of N-glycans. Given the association of FUT8 with various diseases, including cancer, selective FUT8 inhibitors applicable to in vivo or cell-based systems are highly sought-after. Herein, we report the discovery of a compound that selectively inhibits FUT8 in cell-based assays. High-throughput screening revealed a FUT8-inhibiting pharmacophore, and further structural optimization yielded an inhibitor with a KD value of 49 nM. Notably, this binding occurs only in the presence of GDP (a product of the enzymatic reaction catalyzed by FUT8). Mechanistic studies suggested that this inhibitor generates a highly reactive naphthoquinone methide derivative at the binding site in FUT8, which subsequently reacts with FUT8. Furthermore, prodrug derivatization of this inhibitor improved its stability, enabling suppression of core fucose expression and subsequent EGFR and T-cell signaling in cell-based assays, paving the way for the development of drugs targeting core fucosylation.
Insights
Researchers discovered a novel compound that selectively inhibits alpha-1,6-fucosyltransferase (FUT8) in cell-based assays. This selective FUT8 inhibitor shows promise for developing new drugs targeting diseases associated with core fucosylation.
Area of Science:
- Biochemistry
- Glycobiology
- Medicinal Chemistry
Background:
- Core fucosylation, catalyzed by alpha-1,6-fucosyltransferase (FUT8), modifies N-glycans.
- Dysregulated FUT8 activity is linked to various diseases, including cancer.
- Selective FUT8 inhibitors are crucial for therapeutic development.
Purpose of the Study:
- To discover and characterize a novel, selective inhibitor of FUT8.
- To evaluate the inhibitor's efficacy in cell-based systems.
- To explore its potential for therapeutic applications.
Main Methods:
- High-throughput screening to identify a FUT8-inhibiting pharmacophore.
- Structural optimization to enhance inhibitor potency (KD = 49 nM).
- Mechanistic studies to elucidate the inhibition mechanism and prodrug derivatization for improved stability.
Main Results:
- A selective FUT8 inhibitor was identified and optimized.
- The inhibitor binds in a GDP-dependent manner.
- Prodrug derivatization enhanced stability, enabling suppression of core fucose expression.
- Inhibitor demonstrated suppression of EGFR and T-cell signaling in cell-based assays.
Conclusions:
- A novel, potent, and selective FUT8 inhibitor was developed.
- The inhibitor's mechanism involves generating a reactive intermediate.
- The optimized inhibitor shows potential for targeting diseases involving aberrant core fucosylation.
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