Triazole-Based Inhibitors of the Wnt/β-Catenin Signaling Pathway Improve Glucose and Lipid Metabolisms in Diet-Induced Obese Mice

Abstract

Wnt/β-catenin signaling pathway is implicated in the etiology and progression of metabolic disorders. While lines of genetic evidence suggest that blockage of this pathway yields favorable outcomes in treating such ailments, few inhibitors have been used to validate the promising genetic findings. Here, we synthesized and characterized a novel class of triazole-based Wnt/βcatenin signaling inhibitors, and assessed their effects on energy metabolism. One of the top inhibitors, compound 3a, promoted Axin stabilization, which led to the proteasome degradation of β-catenin and subsequent inhibition of the Wnt/β-catenin signaling in cells. Treatment of hepatocytes and high fat diet-fed mice with compound 3a resulted in significantly decreased hepatic lipid accumulation. Moreover, compound 3a improved glucose tolerance of high fat dietfed mice without noticeable toxicity, while downregulating the genes involved in the glucose and fatty acid anabolism. The new inhibitors are expected to be further developed for the treatment of metabolic disorders.

RETRACTED: Pyrvinium Treatment Confers Hepatic Metabolic Benefits via β-Catenin Downregulation and AMPK Activation

“…Cell lysates were prepared using NP-40 lysis buffer as previously described [ 16 ]. The lysate was centrifuged at 14,000× g for 15 min at 4 °C.…”

“…Cell lysates were prepared using NP-40 lysis buffer as previously described [16]. The lysate was centrifuged at 14,000× g for 15 min at 4 • C. Bicinchoninic acid (BCA) assay was used to normalize protein concentrations across the samples, and the proteins were resolved on a 7.5-12% SDS-PAGE gels.…”

“…One approach to elucidate the role of β-catenin in glucose, lipid metabolism, and its therapeutic implication in metabolic complications is through the use of its small molecule modulators [ 15 , 16 ]. Only a few studies have explored this angle.…”

Synthesis, crystal structure and Hirshfeld surface analysis of N-(4-chlorophenyl)-5-cyclopropyl-1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxamide

“…A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides was screened for their antiproliferative activity and showed promising cytotoxicity against lung cancer cell line A549 (Prasad et al, 2019). In addition to the antitumor studies, 1H-1,2,3-triazole-4-carboxamides exhibit other biological activities such as fungicidal (Wang et al, 2014), antiviral (Krajczyk et al, 2014) and antimicrobial (Jadhav et al, 2017) activities and were found to be inhibitors of the Wnt/catenin signalling pathway (Obianom et al, 2019). It should be noted that the diversity of such compounds can be obtained by amidation of 1H-1,2,3-triazole-4-carboxylic acids prepared by convenient Dimroth synthesis and further modifications (Pokhodylo et al, 2009(Pokhodylo et al, , 2017(Pokhodylo et al, , 2018Pokhodylo, Savka et al, 2010;.…”

<p>Discovery of a Novel Benzenesulfonamide Analogue That Inhibits Proliferation and Metastasis Against Ovarian Cancer OVCAR-8 Cells</p>

“…23 Some 1,2,3-triazoles recently described as inhibitors of the wnt/β-catenin signaling pathway. 24 In addition, celecoxib as a sulfonamide selective COX-2 inhibitor inhibited human colon cancer cell proliferation by suppressing the Wnt/β-catenin signaling pathway. 25 Because of the same 1,2,3-triazole scaffold in the hybrid 7c, we also explored its effects on the wnt/β-catenin signaling pathway.…”