Inhibition of tankyrase by a novel small molecule significantly attenuates prostate cancer cell proliferation.
Tankyrase (TNKS) is a crucial mediator of Wnt signal transduction and has been recognized as a novel molecular target for Wnt-pathway dependent cancer. TNKS is stabilized by the ubiquitin-specific protease 25 (USP25). The effect of disruption of the interaction between TNKS and USP25 by small molecules on prostate cancer proliferation ... is unknown. In this study we conducted a hierarchical virtual screening with more than 200,000 compounds on the characterized structures of the USP25/TNKS-ARC5 protein complex. In silico analysis and in vitro validation revealed that a small molecule, called C44, binds to the protein-protein interaction (PPI) interface of TNKS and USP25. We show that C44 disrupts the interaction between TNKS and USP25 leading to a higher half-life of AXIN and the breakdown of -catenin protein. We also show that the selective inhibition of the TNKS-USP25 interaction by C44 significantly reduces proliferation of prostate cancer cells in vitro and in vivo. Our study reveals a new PPI inhibitor that lowers the stability of TNKS protein and inhibits Wnt pathway signaling. C44 is a promising new drug for the treatment of Wnt-pathway dependent prostate cancer.
Mesh Terms:
Animals, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Humans, Male, Mice, Prostatic Neoplasms, Protein Binding, Small Molecule Libraries, Tankyrases, Ubiquitin Thiolesterase, Wnt Signaling Pathway, Xenograft Model Antitumor Assays
Animals, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Humans, Male, Mice, Prostatic Neoplasms, Protein Binding, Small Molecule Libraries, Tankyrases, Ubiquitin Thiolesterase, Wnt Signaling Pathway, Xenograft Model Antitumor Assays
Cancer Lett.
Date: Dec. 28, 2018
PubMed ID: 30472184
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