title: Development of orally active inhibitors of protein and cellular fucosylation.
abstract: The key role played by fucose in glycoprotein and cellular function has prompted significant research toward identifying recombinant and biochemical strategies for blocking its incorporation into proteins and membrane structures. Technologies surrounding engineered cell lines have evolved for the inhibition of in vitro fucosylation, but they are not applicable for in vivo use and drug development. To address this, we screened a panel of fucose analogues and identified 2-fluorofucose and 5-alkynylfucose derivatives that depleted cells of GDP-fucose, the substrate used by fucosyltransferases to incorporate fucose into protein and cellular glycans. The inhibitors were used in vitro to generate fucose-deficient antibodies with enhanced antibody-dependent cellular cytotoxicity activities. When given orally to mice, 2-fluorofucose inhibited fucosylation of endogenously produced antibodies, tumor xenograft membranes, and neutrophil adhesion glycans. We show that oral 2-fluorofucose treatment afforded complete protection from tumor engraftment in a syngeneic tumor vaccine model, inhibited neutrophil extravasation, and delayed the outgrowth of tumor xenografts in immune-deficient mice. The results point to several potential therapeutic applications for molecules that selectively block the endogenous generation of fucosylated glycan structures.
authors.affiliation: Seattle Genetics, Bothell, WA 98021, USA. nokeley@seagen.com
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Okeley
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Alley
authors.forename: Martha E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Tamar E
authors.initials: TE
authors.lastname: Boursalian
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Burke
authors.forename: Kim M
authors.initials: KM
authors.lastname: Emmerton
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
authors.forename: Kerry
authors.initials: K
authors.lastname: Klussman
authors.forename: Che-Leung
authors.initials: CL
authors.lastname: Law
authors.forename: Django
authors.initials: D
authors.lastname: Sussman
authors.forename: Brian E
authors.initials: BE
authors.lastname: Toki
authors.forename: Lori
authors.initials: L
authors.lastname: Westendorf
authors.forename: Weiping
authors.initials: W
authors.lastname: Zeng
authors.forename: Xinqun
authors.initials: X
authors.lastname: Zhang
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Benjamin
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D016466:CHO Cells; D019496:Cancer Vaccines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D005260:Female; D005643:Fucose / Q000737:chemistry / Q000494:pharmacology*; D005647:Fucosyltransferases / Q000037:antagonists & inhibitors*; D006154:Guanosine Diphosphate Fucose / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D011134:Polysaccharides; D006154:Guanosine Diphosphate Fucose; D005643:Fucose; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase