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Updated: May 10, 2026
Large Scale Zebrafish-Based In vivo Small Molecule Screen
Published on: December 30, 2010
Ultra-large scale virtual screening identifies a small molecule inhibitor of the Wnt transporter Wntless
Jia Yu1, Pei-Ju Liao1, Thomas H Keller2
1Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
Abstract:
Wnts are lipid-modified glycoproteins that play key roles in both embryonic development and adult homeostasis. Wnt signaling is dysregulated in many cancers and preclinical data shows that targeting Wnt biosynthesis and secretion can be effective in Wnt-addicted cancers. An integral membrane protein known as Wntless (WLS/Evi) is essential for Wnt secretion. However, WLS remains undrugged thus far. The cryo-EM structure of WLS in complex with WNT8A shows that WLS has a druggable G-protein coupled receptor (GPCR) domain. Using Active Learning/Glide, we performed an ultra-large scale virtual screening from Enamine's REAL 350/3 Lead-Like library containing nearly 500 million compounds. 68 hits were examined after on-demand synthesis in cell-based Wnt reporter and other functional assays. ETC-451 emerged as a potential first-in-class WLS inhibitor. ETC-451 blocked WLS-WNT3A interaction and decreased Wnt-addicted pancreatic cancer cell line proliferation. The current hit provides a starting chemical scaffold for further structure or ligand-based drug discovery targeting WLS.
Insights
Researchers identified ETC-451, a novel Wntless (WLS) inhibitor, offering a new therapeutic strategy for Wnt-addicted cancers. This discovery targets Wnt secretion, a key pathway in cancer development and progression.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Wnt signaling is crucial for development and homeostasis but dysregulated in cancers.
- Targeting Wnt secretion is a promising strategy for Wnt-addicted cancers.
- Wntless (WLS) is essential for Wnt secretion and an undrugged target.
Purpose of the Study:
- To identify novel inhibitors of Wntless (WLS) for cancer therapy.
- To explore the druggability of the WLS protein.
Main Methods:
- Utilized cryo-electron microscopy (cryo-EM) to determine the structure of WLS in complex with WNT8A.
- Performed large-scale virtual screening of ~500 million compounds using Active Learning/Glide.
- Conducted cell-based assays and functional analysis on synthesized compounds.
Main Results:
- Identified ETC-451 as a first-in-class WLS inhibitor.
- ETC-451 demonstrated inhibition of WLS-WNT3A interaction.
- ETC-451 reduced proliferation in Wnt-addicted pancreatic cancer cell lines.
Conclusions:
- WLS possesses a druggable GPCR domain, making it a viable therapeutic target.
- ETC-451 represents a promising starting scaffold for WLS-targeted drug discovery.
- This research opens new avenues for treating Wnt-driven cancers.
