Altered cellular metabolism is a hallmark of
cancer pathogenesis and progression; for example, a near-universal feature of
cancer is increased metabolic flux through the
hexosamine biosynthetic pathway (HBP). This pathway produces
uridine diphosphate N-acetylglucosamine (
UDP-GlcNAc), a potent oncometabolite that drives multiple facets of
cancer progression. In this study, we synthesized and evaluated peracetylated
hexosamine analogs designed to reduce flux through the HBP. By screening a panel of analogs in
pancreatic cancer and
glioblastoma multiform (GBM) cells, we identified Ac4Glc2Bz─a benzyl-modified GlcNAc mimetic─as an antiproliferative
cancer drug candidate that down-regulated oncogenic metabolites and reduced GBM cell motility at concentrations non-toxic to non-neoplastic cells. More specifically, the growth inhibitory effects of Ac4Glc2Bz were linked to reduced levels of
UDP-GlcNAc and concomitant decreases in
protein O-GlcNAc modification in both
pancreatic cancer and GBM cells. Targeted metabolomics analysis in GBM cells showed that Ac4Glc2Bz disturbed
glucose metabolism,
amino acid pools, and
nucleotide precursor biosynthesis, consistent with reduced proliferation and other anti-oncogenic properties of this analog. Furthermore, Ac4Glc2Bz reduced the invasion, migration, and stemness of GBM cells. Importantly, normal metabolic functions mediated by
UDP-GlcNAc were not disrupted in non-neoplastic cells, including maintenance of endogenous levels of O-GlcNAcylation with no global disruption of N-
glycan production. Finally, a pilot in vivo study showed that a potential therapeutic window exists where animals tolerated 5- to 10-fold higher levels of Ac4Glc2Bz than projected for in vivo efficacy. Together, these results establish GlcNAc analogs targeting the HBP through salvage mechanisms as a new therapeutic approach to safely normalize an important facet of aberrant
glucose metabolism associated with
cancer.