Research Papers:

Discovery of novel frizzled-7 inhibitors by targeting the receptor’s transmembrane domain

Wei Zhang _, Wenyan Lu, Subramaniam Ananthan, Mark J. Suto and Yonghe Li

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Oncotarget. 2017; 8:91459-91470. https://doi.org/10.18632/oncotarget.20665

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Wei Zhang1, Wenyan Lu2, Subramaniam Ananthan1, Mark J. Suto1 and Yonghe Li2

1Department of Chemistry, Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35205, United States

2Department of Oncology, Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35205, United States

Correspondence to:

Wei Zhang, email: [email protected]

Yonghe Li, email: [email protected]

Keywords: frizzled, Wnt/β-catenin, inhibitor, virtual screening, cancer

Received: March 29, 2017    Accepted: June 28, 2017    Published: September 06, 2017


Frizzled (Fzd) proteins are seven transmembrane receptors that belong to a novel and separated family of G-protein-coupled receptors (GPCRs). The Fzd receptors can respond to Wnt proteins to activate the canonical β-catenin pathway which is important for both initiation and progression of cancers. Disruption of the Wnt/β-catenin signal thus represents an opportunity for rational cancer prevention and therapy. Of the 10 members of the Fzd family, Fzd7 is the most important member involved in cancer development and progression. In the present studies, we applied structure-based virtual screening targeting the transmembrane domain (TMD) of Fzd7 to select compounds that could potentially bind to the Fzd7-TMD and block the Wnt/Fzd7 signaling and further evaluated them in biological assays. Six small molecule compounds were confirmed as Fzd7 inhibitors. The best hit, SRI37892, significantly blocked the Wnt/Fzd7 signaling with IC50 values in the sub-micromolar range and inhibited cancer cell proliferation with IC50 values around 2 μM. Our results provide the first proof of concept of targeting Fzd-TMD for the development of Wnt/Fzd modulators. The identified small molecular Fzd7 inhibitors can serve as a useful tool for studying the regulation mechanism(s) of Wnt/Fzd7 signaling as well as a starting point for the development of cancer therapeutic agents.

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