2. Academic Validation
  3. Harnessing the bishomolithocholic acid scaffold for selective sialyltransferase inhibition: A targeted approach to suppress breast cancer metastasis

Harnessing the bishomolithocholic acid scaffold for selective sialyltransferase inhibition: A targeted approach to suppress breast cancer metastasis

  • Eur J Med Chem. 2025 Aug 5:292:117674. doi: 10.1016/j.ejmech.2025.117674.
Ser John Lynon P Perez 1,  Zih-Fan Hsu 2,  Tzu-Ting Chang 3,  Chia-Ling Chen 4,  Wen-Shan Li 5
Affiliations

Affiliations

  • 1 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan; Department of Applied Chemistry, National Yang Ming Chiao Tung University, Hsinchu, 300, Taiwan; Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, 115, Taiwan.
  • 2 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan; Department of Chemistry, National Taiwan Normal University, Taipei, 116, Taiwan.
  • 3 Biomedical Translation Research Center, Academia Sinica, Taipei, 115, Taiwan.
  • 4 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan.
  • 5 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan; Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, 115, Taiwan; Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan. Electronic address: wenshan@gate.sinica.edu.tw.
PMID: 40324300 DOI: 10.1016/j.ejmech.2025.117674
Abstract

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.

Keywords

Bishomolithocholic acid; Breast cancer metastasis; Integrin-FAK-Paxillin axis; N-glycan sialylation; ST6GAL1; Sialyltransferase inhibitor.

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