A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma
文献类型：期刊论文
| 作者 | Mou, Jiahui1; Chen, Runqiu2,3; Dai, Zihao1; Yang, Hao4,5; Suo, Feiyashan6; Li, Yifan6; Ye, Yangxu1; Fang, Pengfei1,6; Bai, Fang4,5; Zhao, Yachen6 |
| 刊名 | ACS CENTRAL SCIENCE
 |
| 出版日期 | 2025-09-03 |
| 页码 | 15 |
| ISSN号 | 2374-7943 |
| DOI | 10.1021/acscentsci.5c00939 |
| 英文摘要 | 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 alpha-2,3/2,6-sialylation in PDAC cells (IC50 approximate to 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. Mechanistic studies establish that the therapeutic efficacy of Y-320 depends on the coordinated engagement between CD8(+) T cell and macrophage. Importantly, Y-320 synergizes with anti-PD-1 therapy to overcome ICB resistance in PDAC, demonstrating superior tumor suppression compared to monotherapies. Our findings demonstrate that Y-320 shows promise for use as a therapeutic agent for cancer and validates sialylation inhibition as a novel glycoimmune checkpoint strategy for PDAC and other immunotherapy-resistant malignancies. |
| WOS关键词 | T-CELL PROLIFERATION ; SIALYLTRANSFERASE INHIBITORS ; CANCER ; ACID ; GLYCOSYLATION ; DETERMINES ; MECHANISMS ; TOLERANCE ; DISCOVERY ; CARCINOMA |
| 资助项目 | National Natural Science Foundation of China[22407134] ; National Natural Science Foundation of China[92478001] ; National Natural Science Foundation of China[2022YFA1304700] ; National Key R&D Program of China[XDB1060000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[2024M753383] ; China Postdoctoral Science Foundation[GZB20230797] ; Postdoctoral Fellowship Program of CPSF |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001564199800001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321408]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Long, Yiru; Gong, Likun; Wang, Jing; Yu, Biao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, Shanghai 200032, Peoples R China 2.Fudan Univ, Shanghai Inst Infect Dis & Biosecur, Shanghai 200032, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Chem & Mat Sci, Hangzhou 310024, Peoples R China 7.China Med Univ, Sch Publ Hlth, Shenyang 110122, Peoples R China |
| 推荐引用方式 GB/T 7714 | Mou, Jiahui,Chen, Runqiu,Dai, Zihao,et al. A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma[J]. ACS CENTRAL SCIENCE,2025:15. |
| APA | Mou, Jiahui.,Chen, Runqiu.,Dai, Zihao.,Yang, Hao.,Suo, Feiyashan.,...&Yu, Biao.(2025).A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma.ACS CENTRAL SCIENCE,15. |
| MLA | Mou, Jiahui,et al."A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma".ACS CENTRAL SCIENCE (2025):15. |
入库方式： OAI收割
来源：上海药物研究所
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