Novel PORCN inhibitor WHN-88 targets Wnt/β-catenin pathway and prevents the growth of Wnt-driven cancers

Eur J Pharmacol. 2023 Apr 15:945:175628. doi: 10.1016/j.ejphar.2023.175628. Epub 2023 Feb 28.


Wnt/β-catenin signaling pathway is a classical and crucial oncogenic pathway in many carcinomas, and Porcupine (PORCN) is an O-acyltransferase, which is indispensable and highly specific for catalyzing palmitoylation of Wnt ligands and facilitating their secretion and biofunction. Targeting PORCN provides a promising approach to specifically cure Wnt-driven cancers from the root. In this study, we designed series of pyridonyl acetamide compounds, and discovered a novel PORCN inhibitor WHN-88 with a unique di-iodinated pyridone structural fragment, which is significantly different from the reported inhibitors. We demonstrated that WHN-88 effectively abolished palmitoylation of Wnt ligands and prevented their secretion and the subsequent Wnt/β-catenin signaling transduction. Further experiments showed that, at well-tolerated doses, WHN-88 remarkably suppressed the spontaneous occurrence and growth of MMTV-Wnt1 murine breast tumors. Consistently, WHN-88 also notably restrained the progress of xenografted Wnt-driven human tumors, including PA-1 teratocarcinoma with high autocrine Wnt signaling and Aspc-1 pancreatic carcinoma with Wnt-sensitizing RNF43 mutation. Additionally, we disclosed that WHN-88 inhibited cancer cell stemness obviously. Together, we verified WHN-88 is a novel PORCN inhibitor with potent efficacy against the Wnt-driven cancers. Our findings enriched the structural types of PORCN inhibitors, and facilitated the development and application of PORCN inhibiting therapy in clinic.

Keywords: PORCN inhibitor; Palmitoylation; WHN-88; Wnt-driven cancers.

MeSH terms

  • Acyltransferases / chemistry
  • Acyltransferases / genetics
  • Acyltransferases / metabolism
  • Animals
  • Humans
  • Ligands
  • Membrane Proteins / metabolism
  • Mice
  • Mutation
  • Pancreatic Neoplasms*
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism


  • Acyltransferases
  • beta Catenin
  • Ligands
  • Membrane Proteins
  • PORCN protein, human
  • Porcn protein, mouse