2. Academic Validation
  3. Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening

Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening

  • ACS Chem Biol. 2025 Jun 20;20(6):1319-1332. doi: 10.1021/acschembio.5c00155.
Xinyu Yang 1 2,  Yanbei Li 2 3 4 5,  Jingyi Zhou 2 6 7,  Yuanyang Zhou 8 7,  Kexin Lin 1 2,  Shuqing Chu 1 2,  Jingyi Meng 1 2,  Xinyi Ma 1 2,  Yuan Zhu 1 2,  Xutong Li 2 3,  Dan Teng 2 3,  Mingyue Zheng 1 2 3 7,  Sulin Zhang 2 3
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 6 School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 7 Lingang Laboratory, Shanghai 200031, China.
  • 8 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
PMID: 40418194 DOI: 10.1021/acschembio.5c00155
Abstract

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/β-catenin signaling pathway (IC50 = 155.4 nM) and exhibited high binding affinity to PORCN (KD = 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.

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