A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains refractory to current immune checkpoint blockade (ICB) therapies, necessitating innovative therapeutic strategies. Emerging evidence implicates aberrant sialoglycan upregulation as a key mediator of immune evasion in PDAC. Herein, we report Y-320, a highly potent oral sialylation inhibitor discovered through high-throughput screening. Y-320 suppresses α-2,3/2,6-sialylation in PDAC cells (IC₅₀ ≈ 200 nM) with >300-fold higher activity than the known pan-inhibitor P-3F_ax-Neu5Ac. Structural analyses reveal competitive occupation of multiple sialyltransferases' substrate-binding pockets as Y-320's action mechanism. In vivo, Y-320 significantly inhibits tumor growth and remodels the tumor immune microenvironment. Mechan

SUBMITTER: Mou J 

PROVIDER: S-EPMC12550625 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature