Development of a FUT8 Inhibitor with Cellular Inhibitory Properties
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 K<sub>D</sub> 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.
Authors
- Satomi Kasahara
- Kazuya Kabayama (ORCID: https://orcid.org/0000-0002-7583-5454)
- Shinichiro Shinzaki (ORCID: https://orcid.org/0000-0002-7051-618X)
- Sergey Y. Vakhrushev (ORCID: https://orcid.org/0000-0002-0418-5765)
- Shinji Takamatsu (ORCID: https://orcid.org/0000-0003-1996-7740)
- Luis M. González de la Garza (ORCID: https://orcid.org/0000-0003-3791-2997)
- Akiko Asakura (ORCID: https://orcid.org/0009-0004-0283-070X)
- Yoshiyuki Manabe (ORCID: https://orcid.org/0000-0002-5515-3923)
- Yoshihiro Kamada
- Ramón Hurtado‐Guerrero (ORCID: https://orcid.org/0000-0002-3122-9401)
- Eiji Miyoshi (ORCID: https://orcid.org/0000-0002-9430-2362)
- Koichi Fukase (ORCID: https://orcid.org/0000-0001-8844-0710)
- Tomoyuki Takebe
- Koki Hizume
Institutions
- University of Copenhagen (DK)
- Universidad de Zaragoza (ES)
- Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo (ES)
- Hyogo University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2024-09-28
- DOI
- https://doi.org/10.1002/anie.202414682
- Citations
- 9
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- Japan Agency for Medical Research and Development
- Fundación Agencia Aragonesa para la Investigación y el Desarrollo
- Gobierno de Aragón
- Japan Society for the Promotion of Science
- European Regional Development Fund
- Agencia Estatal de Investigación
- Core Research for Evolutional Science and Technology
- Fusion Oriented REsearch for disruptive Science and Technology