Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Mook, Robert A., Jr.¹  Wang, Jiangbo¹  Ren, Xiu-Rong¹  Piao, Hailan¹  Lyerly, H. Kim²  Chen, Wei¹ 

[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[2] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA

关键词: Niclosamide;    Wnt signaling inhibitor;    Small molecule;    Triazole derivatives;    beta-Catenin;    Cancer;   

DOI  :  10.1016/j.bmcl.2018.11.022

来源: Elsevier

【 摘 要 】

Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/beta-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/beta-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/beta-catenin signaling to identify a new structural class of Wnt/beta-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives inter-nalized Frizzled-1 GFP receptors, inhibited Wnt/beta-catenin signaling in the TOPflash assay and reduced Wnt/beta-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/beta-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/beta-catenin inhibitors.

【 授权许可】

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