Harnessing the Bishomolithocholic Acid Scaffold for Selective Sialyltransferase Inhibition: A Targeted Approach to Suppress Breast Cancer Metastasis

ST6GAL1 plays a crucial role in the progression of triple-negative breast cancer (TNBC), highlighting its potential as a therapeutic target for this aggressive cancer subtype. Due to the high metastatic potential of TNBC and the limitations of current therapies, selective and potent ST6GAL1 inhibitors are urgently needed. In this study, a scaffold-hopping approach from lithocholic acid to bishomolithocholic acid successfully led to the discovery of novel ST6GAL1 inhibitors, SPP-037 and HZF01, with enhanced biological activity and selectivity. Both compounds significantly inhibited MDA-MB-231 cell migration, HUVEC tube formation, tumor growth, and metastasis in vitro and in vivo. Molecular docking studies revealed key interactions between the ST inhibitors and ST6GAL1, supporting their enhanced selectivity and binding affinity. Additionally, SPP-037 and HZF01 were found to block integrin α2,6-sialylation, disrupting integrin activation and downstream signaling pathways involving the phosphorylation of focal adhesion kinase (FAK) and paxillin, which are critical for cell migration. These results underscore the potential of targeting ST6GAL1 to suppress tumor progression and metastasis, offering a promising avenue for treating aggressive breast cancer.