Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis

Abstract

We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.

Small molecule inhibitors of mammalian glycosylation

“…In contrast to other compounds, FCW34 exhibited no inhibition of ST3GAL1 at concentrations lower than 500 μM. Moreover, this molecule was able to inhibit breast cancer tumour growth in vivo in mice [208] .…”

p-Coumaric acid, Kaempferol, Astragalin and Tiliroside Influence the Expression of Glycoforms in AGS Gastric Cancer Cells

“…Sokolova et al [ 43 ] proposed NF-κB as an agent that regulates many genes promoting gastric carcinogenesis. Fu et al [ 44 ] provided evidence that sialyltransferases’ inhibition by NF-κB signaling pathway reduces breast cancer cell metastasis. Other authors also noted relationships between NF-κB-mediated signaling with glycosylation changes in cancers [ 8 ].…”

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

“…Recently, Fu and colleagues employed the “LCA extension strategy”, in which the cyclopentane ring side chain of Lith-O-Asp was extended with one or more ethylene glycol units to generate isozyme-specific sialyltransferase inhibitors [ 172 ]. Within the second-generation ST inhibitors, FCW34 exhibited good pharmacokinetic characteristics and a great permeability potency [ 172 ]. FCW34 was shown to reduce breast cancer cell migration by suppressing α2,3-N-ST3GAL3-catalyzed N-glycoprotein sialylation of β-integrins.…”

“…FCW34 was shown to reduce breast cancer cell migration by suppressing α2,3-N-ST3GAL3-catalyzed N-glycoprotein sialylation of β-integrins. Also, FCW34 was found to inhibit tumor growth and metastasis in a mouse model of triple negative breast cancer, and to suppress angiogenic activity in transgenic zebrafish models [ 172 ], suggesting that it could represent a reasonable therapeutic approach for sialyltransferases-driven breast cancer.…”