Inhibition of tankyrase by a novel small molecule significantly attenuates prostate cancer cell proliferation. (28th February 2019)

• Record Type: Journal Article
• Authors: Cheng, Honglin; Li, Xin; Wang, Chuanlin; Chen, Yujie; Li, Sijiang; Tan, Jincai; Tan, Bing; He, Yunfeng
• Is Part Of: Cancer letters. Volume 443(2019)
• Page Start: 80
• Page End: 90
• Publication Date: 2019-02-28
• Subjects: TNKS inhibitor -- Wnt signaling -- Protein-protein interaction -- Prostate cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.11.013
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: The compound C44 was screened out from a database with over 200, 000 compounds based on characterized structures of USP25/TNKS-ARC5. C44 was validated to prolong the halflife of AXIN and increase β-catenin degradation through promoting the destabilization of TNKS. C44 was showed to the selectively inhibit TNKS-USP25 interaction, effectively reduced prostate cancer cell proliferation and tumor growth.