2. Academic Validation
  3. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

  • Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. doi: 10.1073/pnas.1314239110.
Jun Liu 1,  Shifeng Pan,  Mindy H Hsieh,  Nicholas Ng,  Fangxian Sun,  Tao Wang,  Shailaja Kasibhatla,  Alwin G Schuller,  Allen G Li,  Dai Cheng,  Jie Li,  Celin Tompkins,  AnneMarie Pferdekamper,  Auzon Steffy,  Jane Cheng,  Colleen Kowal,  Van Phung,  Guirong Guo,  Yan Wang,  Martin P Graham,  Shannon Flynn,  J Chad Brenner,  Chun Li,  M Cristina Villarroel,  Peter G Schultz,  Xu Wu,  Peter McNamara,  William R Sellers,  Lilli Petruzzelli,  Anthony L Boral,  H Martin Seidel,  Margaret E McLaughlin,  Jianwei Che,  Thomas E Carey,  Gary Vanasse,  Jennifer L Harris
Affiliations

Affiliation

  • 1 Genomics Institute of Novartis Research Foundation, San Diego, CA 92121.
PMID: 24277854 DOI: 10.1073/pnas.1314239110
Abstract

Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt Inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic Breast Cancer Models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck Cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.

Keywords

HNSCC; Wnt inhibition; β-catenin.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-17545
    99.92%, PORCN Inhibitor