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

Publication ,  Journal Article
Mook, RA; Wang, J; Ren, X-R; Piao, H; Lyerly, HK; Chen, W
Published in: Bioorg Med Chem Lett
January 15, 2019

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.

Duke Scholars

Published In

Bioorg Med Chem Lett

DOI

EISSN

1464-3405

Publication Date

January 15, 2019

Volume

29

Issue

2

Start / End Page

317 / 321

Location

England

Related Subject Headings

  • Wnt Signaling Pathway
  • Triazoles
  • Structure-Activity Relationship
  • Niclosamide
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HEK293 Cells
  • Dose-Response Relationship, Drug
  • Cell Line, Tumor
 

Citation

APA
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Mook, R. A., Wang, J., Ren, X.-R., Piao, H., Lyerly, H. K., & Chen, W. (2019). Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype. Bioorg Med Chem Lett, 29(2), 317–321. https://doi.org/10.1016/j.bmcl.2018.11.022
Mook, Robert A., Jiangbo Wang, Xiu-Rong Ren, Hailan Piao, H Kim Lyerly, and Wei Chen. “Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.Bioorg Med Chem Lett 29, no. 2 (January 15, 2019): 317–21. https://doi.org/10.1016/j.bmcl.2018.11.022.
Mook RA, Wang J, Ren X-R, Piao H, Lyerly HK, Chen W. Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype. Bioorg Med Chem Lett. 2019 Jan 15;29(2):317–21.
Mook, Robert A., et al. “Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.Bioorg Med Chem Lett, vol. 29, no. 2, Jan. 2019, pp. 317–21. Pubmed, doi:10.1016/j.bmcl.2018.11.022.
Mook RA, Wang J, Ren X-R, Piao H, Lyerly HK, Chen W. Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype. Bioorg Med Chem Lett. 2019 Jan 15;29(2):317–321.
Journal cover image

Published In

Bioorg Med Chem Lett

DOI

EISSN

1464-3405

Publication Date

January 15, 2019

Volume

29

Issue

2

Start / End Page

317 / 321

Location

England

Related Subject Headings

  • Wnt Signaling Pathway
  • Triazoles
  • Structure-Activity Relationship
  • Niclosamide
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HEK293 Cells
  • Dose-Response Relationship, Drug
  • Cell Line, Tumor