中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening

文献类型：期刊论文

作者Yang, Xinyu7,8; Li, Yanbei4,5,6,7; Zhou, Jingyi2,3,7; Zhou, Yuanyang1,2; Lin, Kexin7,8; Chu, Shuqing7,8; Meng, Jingyi7,8; Ma, Xinyi7,8; Zhu, Yuan7,8; Li, Xutong6,7
刊名ACS CHEMICAL BIOLOGY
出版日期2025-05-26
卷号20期号:6页码:1319-1332
ISSN号1554-8929
DOI10.1021/acschembio.5c00155
英文摘要Dysregulated activation of the Wnt pathway is closely associated with oncogenesis and the progression of various cancers. Palmitoylation catalyzed by porcupine (PORCN) is essential for the secretion of Wnts and the activation of the Wnt pathway. Given its critical role in regulating Wnt signaling, PORCN has been recognized as a promising therapeutic target for cancers driven by aberrant Wnt pathway activation. Herein, we explored the binding modes of reported inhibitors with different scaffolds using molecular docking and molecular dynamics simulations, establishing an optimized structure-based virtual screening model, which discovered a novel PORCN inhibitor, Y-99. Y-99 demonstrated promising inhibitory activity against the Wnt/beta-catenin signaling pathway (IC50 = 155.4 nM) and exhibited high binding affinity to PORCN (K D = 33.1 nM). Notably, Y-99 exerted a significant antiproliferation effect in Wnt-addicted tumor cell lines, accompanied by reduced LRP6 phosphorylation and downregulation of Wnt-related gene expression, including AXIN2 and CCND1. Taken together, these findings highlight that Y-99, which was identified through in silico screening and validated in vitro, is a promising PORCN inhibitor, which has the potential for further research and development.
WOS关键词CELL-GROWTH ; WNT ; PORCUPINE ; PATHWAY ; POTENT ; ACYLATION ; DOCKING ; COMPLEX ; CANCER
资助项目Natural Science Foundation of Shanghai Municipality[2023YFC2305904] ; Natural Science Foundation of Shanghai Municipality[2022YFC3400504] ; National Key Research and Development Program of China[T2225002] ; National Key Research and Development Program of China[82273855] ; National Key Research and Development Program of China[82474143] ; National Key Research and Development Program of China[82204278] ; National Natural Science Foundation of China[XDB0830200] ; National Natural Science Foundation of China[XDB0830203] ; Strategic Priority Research Program of the Chinese Academy of Sciences[2023296] ; Youth Innovation Promotion Association CAS[22ZR1474300] ; Natural Science Foundation of Shanghai[2023QNRC001] ; Young Elite Scientists Sponsorship Program by CAST[GZC20232846] ; CPSF[2024M763419] ; China Postdoctoral Science Foundation
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:001494672000001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/317953]  
专题新药研究国家重点实验室
通讯作者Teng, Dan; Zheng, Mingyue; Zhang, Sulin
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
2.Lingang Lab, Shanghai 200031, Peoples R China
3.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
8.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Xinyu,Li, Yanbei,Zhou, Jingyi,et al. Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening[J]. ACS CHEMICAL BIOLOGY,2025,20(6):1319-1332.
APA Yang, Xinyu.,Li, Yanbei.,Zhou, Jingyi.,Zhou, Yuanyang.,Lin, Kexin.,...&Zhang, Sulin.(2025).Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening.ACS CHEMICAL BIOLOGY,20(6),1319-1332.
MLA Yang, Xinyu,et al."Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening".ACS CHEMICAL BIOLOGY 20.6(2025):1319-1332.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。