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

Journal Article (Journal Article)

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/β-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/β-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/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-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/β-catenin inhibitors.

Full Text

Duke Authors

Cited Authors

  • Mook, RA; Wang, J; Ren, X-R; Piao, H; Lyerly, HK; Chen, W

Published Date

  • January 15, 2019

Published In

Volume / Issue

  • 29 / 2

Start / End Page

  • 317 - 321

PubMed ID

  • 30551901

Pubmed Central ID

  • PMC6688898

Electronic International Standard Serial Number (EISSN)

  • 1464-3405

Digital Object Identifier (DOI)

  • 10.1016/j.bmcl.2018.11.022


  • eng

Conference Location

  • England