Related Experiment Video
Updated: Dec 24, 2025
Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA
Published on: February 23, 2024
Discovery of Novel Inhibitor for WNT/β-Catenin Pathway by Tankyrase 1/2 Structure-Based Virtual Screening
Bo Li1, Jinxia Liang1, Feng Lu1
1Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, China.
Abstract:
Aberrant activation of the WNT/β-catenin signaling pathway is implicated in various types of cancers. Inhibitors targeting the Wnt signaling pathway are intensively studied in the current cancer research field, the outcomes of which remain to be determined. In this study, we have attempted to discover novel potent WNT/β-catenin pathway inhibitors through tankyrase 1/2 structure-based virtual screening. After screening more than 13.4 million compounds through molecular docking, we experimentally verified one compound, LZZ-02, as the most potent inhibitor out of 11 structurally representative top hits. LiCl-induced HEK293 cells containing TOPFlash reporter showed that LZZ-02 inhibited the transcriptional activity of β-catenin with an IC50 of 10 ± 1.2 μM. Mechanistically, LZZ-02 degrades the expression of β-catenin by stabilizing axin 2, thereby diminishing downstream proteins levels, including c-Myc and cyclin D1. LZZ-02 also inhibits the growth of colonic carcinoma cell harboring constitutively active β-catenin. More importantly, LZZ-02 effectively shrinks tumor xenograft derived from colonic cell lines. Our study successfully identified a novel tankyrase 1/2 inhibitor and shed light on a novel strategy for developing inhibitors targeting the WNT/β-catenin signaling axis.
Insights
Researchers discovered LZZ-02, a potent tankyrase 1/2 inhibitor, that targets the WNT/β-catenin pathway. This novel compound degrades β-catenin, inhibiting cancer cell growth and shrinking tumors in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant WNT/β-catenin signaling drives numerous cancers.
- Targeting this pathway is a key area of cancer research.
- Developing effective inhibitors remains a challenge.
Purpose of the Study:
- To identify novel, potent inhibitors of the WNT/β-catenin pathway.
- To utilize structure-based virtual screening for inhibitor discovery.
- To validate tankyrase 1/2 as a therapeutic target.
Main Methods:
- Screened over 13.4 million compounds using molecular docking against tankyrase 1/2.
- Experimentally verified top-hit compounds.
- Assessed inhibitor potency using TOPFlash reporter assays in HEK293 cells.
- Investigated mechanism of action via protein expression analysis.
- Evaluated efficacy in colon cancer cell lines and tumor xenografts.
Main Results:
- Identified LZZ-02 as a potent tankyrase 1/2 inhibitor.
- LZZ-02 inhibited β-catenin transcriptional activity with an IC50 of 10 ± 1.2 μM.
- LZZ-02 induced β-catenin degradation by stabilizing axin 2.
- Reduced levels of downstream proteins c-Myc and cyclin D1.
- Inhibited growth of colon cancer cells and reduced tumor xenograft size.
Conclusions:
- LZZ-02 is a novel, potent tankyrase 1/2 inhibitor.
- LZZ-02 effectively targets the WNT/β-catenin pathway in cancer.
- This study presents a promising strategy for developing WNT/β-catenin inhibitors.
More Related Videos
Related Concept Videos
02:54Canonical Wnt Signaling Pathway
01:41Non-Canonical Wnt Signaling Pathways