000150539 001__ 150539 000150539 005__ 20260112133325.0 000150539 0247_ $$2doi$$a10.1002/anie.202414682 000150539 0248_ $$2sideral$$a142594 000150539 037__ $$aART-2024-142594 000150539 041__ $$aeng 000150539 100__ $$aManabe, Yoshiyuki 000150539 245__ $$aDevelopment of a FUT8 Inhibitor with Cellular Inhibitory Properties 000150539 260__ $$c2024 000150539 5060_ $$aAccess copy available to the general public$$fUnrestricted 000150539 5203_ $$aCore 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. 000150539 536__ $$9info:eu-repo/grantAgreement/EUR/COST-Action/CA18103-INNOGLY$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/E34-R17$$9info:eu-repo/grantAgreement/ES/DGA/LMP58-18$$9info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136362NB-I00 000150539 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es 000150539 590__ $$a16.9$$b2024 000150539 592__ $$a5.55$$b2024 000150539 591__ $$aCHEMISTRY, MULTIDISCIPLINARY$$b15 / 239 = 0.063$$c2024$$dQ1$$eT1 000150539 593__ $$aChemistry (miscellaneous)$$c2024$$dQ1 000150539 593__ $$aCatalysis$$c2024$$dQ1 000150539 594__ $$a27.6$$b2024 000150539 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000150539 700__ $$aTakebe, Tomoyuki 000150539 700__ $$aKasahara, Satomi 000150539 700__ $$aHizume, Koki 000150539 700__ $$aKabayama, Kazuya 000150539 700__ $$aKamada, Yoshihiro 000150539 700__ $$aAsakura, Akiko 000150539 700__ $$aShinzaki, Shinichiro 000150539 700__ $$aTakamatsu, Shinji 000150539 700__ $$aMiyoshi, Eiji 000150539 700__ $$0(orcid)0000-0003-3791-2997$$aGarcía-García, Ana 000150539 700__ $$aVakhrushev, Sergey Y. 000150539 700__ $$0(orcid)0000-0002-3122-9401$$aHurtado-Guerrero, Ramón 000150539 700__ $$aFukase, Koichi 000150539 773__ $$g63, 52 (2024), e202414682 [8 pp.]$$pAngew. Chem. (Int. ed.)$$tAngewandte Chemie (International ed.)$$x1433-7851 000150539 8564_ $$s1630959$$uhttps://zaguan.unizar.es/record/150539/files/texto_completo.pdf$$yVersión publicada 000150539 8564_ $$s2668678$$uhttps://zaguan.unizar.es/record/150539/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000150539 909CO $$ooai:zaguan.unizar.es:150539$$particulos$$pdriver 000150539 951__ $$a2026-01-12-13:09:09 000150539 980__ $$aARTICLE