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

ABSTRACT: 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/?-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/?-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/?-catenin signaling to identify a new structural class of Wnt/?-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/?-catenin signaling in the TOPflash assay and reduced Wnt/?-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/?-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/?-catenin inhibitors.

SUBMITTER: Mook RA

PROVIDER: S-EPMC6688898 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Mook Robert A RA Wang Jiangbo J Ren Xiu-Rong XR Piao Hailan H Lyerly H Kim HK Chen Wei W

Bioorganic & medicinal chemistry letters 20181112 2

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 ...[more]

PMID: 30551901

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Project description:The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.

Dataset Information

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

Publications

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

Similar Datasets

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