Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer

Zhiqing Liu, Pingyuan Wang, Eric A. Wold, Qiaoling Song, Chenyang Zhao, Changyun Wang, Jia Zhou

Research output: Contribution to journalReview articlepeer-review


Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery. From the production and secretion of WNT ligands, their binding to membrane receptors, and the β-catenin destruction complex to the expansive β-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling. Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clinical trials. Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted.

Original languageEnglish (US)
Pages (from-to)4257-4288
Number of pages32
JournalJournal of medicinal chemistry
Issue number8
StatePublished - Apr 22 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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