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

  • Obinna N. Obianom
    Obinna N. Obianom
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
  • Yong Ai
    Yong Ai
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    More by Yong Ai
  • Yingjun Li
    Yingjun Li
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    More by Yingjun Li
  • Wei Yang
    Wei Yang
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    More by Wei Yang
  • Dong Guo
    Dong Guo
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    More by Dong Guo
  • Hong Yang
    Hong Yang
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    More by Hong Yang
  • Srilatha Sakamuru
    Srilatha Sakamuru
    National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892-3375, United States
  • Menghang Xia
    Menghang Xia
    National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892-3375, United States
    More by Menghang Xia
  • Fengtian Xue*
    Fengtian Xue
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    *E-mail: [email protected]. Phone: 410-706-8521 (F.X.).
    More by Fengtian Xue
  • , and 
  • Yan Shu*
    Yan Shu
    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou 510140, China
    *E-mail: [email protected]. Phone: 410-706-7358 (Y.S.).
    More by Yan Shu
Cite this: J. Med. Chem. 2019, 62, 2, 727–741
Publication Date (Web):January 3, 2019
https://doi.org/10.1021/acs.jmedchem.8b01408
Copyright © 2019 American Chemical Society

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    Abstract

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    Wnt/β-catenin signaling pathway is implicated in the etiology and progression of metabolic disorders. Although 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/β-catenin 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 diet-fed mice without noticeable toxicity, while downregulating the genes involved in the glucose and fatty acid anabolisms. The new inhibitors are expected to be further developed for the treatment of metabolic disorders.

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    Cited By

    This article is cited by 12 publications.

    1. Wei Yang, Yingjun Li, Yong Ai, Obinna N. Obianom, Dong Guo, Hong Yang, Srilatha Sakamuru, Menghang Xia, Yan Shu, Fengtian Xue. Pyrazole-4-Carboxamide (YW2065): A Therapeutic Candidate for Colorectal Cancer via Dual Activities of Wnt/β-Catenin Signaling Inhibition and AMP-Activated Protein Kinase (AMPK) Activation. Journal of Medicinal Chemistry 2019, 62 (24) , 11151-11164. https://doi.org/10.1021/acs.jmedchem.9b01252
    2. Ruchi Yadav, Bhumika Patel. Insights on effects of Wnt pathway modulation on insulin signaling and glucose homeostasis for the treatment of type 2 diabetes mellitus: Wnt activation or Wnt inhibition?. International Journal of Biological Macromolecules 2024, 261 , 129634. https://doi.org/10.1016/j.ijbiomac.2024.129634
    3. Mihaela Dascălu, Andreea-Laura Chibac-Scutaru, Gheorghe Roman. Detection of nitroaromatics by a Zn(II)-containing coordination polymer derived from a 1,2,3-triazole-based tricarboxylate ligand. Journal of Molecular Liquids 2023, 386 , 122457. https://doi.org/10.1016/j.molliq.2023.122457
    4. Nazariy Pokhodylo, Nataliya Finiuk, Olha Klyuchivska, Mykola A. Тupychak, Vasyl Matiychuk, Evgeny Goreshnik, Rostyslav Stoika. Novel N-(4-thiocyanatophenyl)-1H-1,2,3-triazole-4-carboxamides exhibit selective cytotoxic activity at nanomolar doses towards human leukemic T-cells. European Journal of Medicinal Chemistry 2022, 241 , 114633. https://doi.org/10.1016/j.ejmech.2022.114633
    5. Yong Ai, Srilatha Sakamuru, Greg Imler, Menghang Xia, Fengtian Xue. Improving the solubility and antileukemia activity of Wnt/β-catenin signaling inhibitors by disrupting molecular planarity. Bioorganic & Medicinal Chemistry 2022, 69 , 116890. https://doi.org/10.1016/j.bmc.2022.116890
    6. Xiaojuan Fei, Meilin Jin, Yuqin Wang, Taotao Li, Zengkui Lu, Zehu Yuan, Huihua Wang, Jian Lu, Kai Quan, Ran Di, Caihong Wei, . Transcriptome reveals key microRNAs involved in fat deposition between different tail sheep breeds. PLOS ONE 2022, 17 (3) , e0264804. https://doi.org/10.1371/journal.pone.0264804
    7. Nazariy Pokhodylo, Nazar Manko, Nataliya Finiuk, Olha Klyuchivska, Vasyl Matiychuk, Mykola Obushak, Rostyslav Stoika. Primary discovery of 1-aryl-5-substituted-1H-1,2,3-triazole-4-carboxamides as promising antimicrobial agents. Journal of Molecular Structure 2021, 1246 , 131146. https://doi.org/10.1016/j.molstruc.2021.131146
    8. N. T. Pokhodylo, V. S. Matiychuk. Evaluation of the antiproliferative activity of selected 1,2,3-triazole-4-carboxylic acids — key fragments and precursors of antitumor 1,2,3-triazole-4-carboxamides. Biopolymers and Cell 2021, 37 (4) , 303-314. https://doi.org/10.7124/bc.000A5C
    9. Karmani Shah, Shivangi Panchal, Bhumika Patel. Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacological Research 2021, 167 , 105532. https://doi.org/10.1016/j.phrs.2021.105532
    10. Shiwei Zhou, Obinna Obianom, Jiangsheng Huang, Dong Guo, Hong Yang, Qing Li, Yan Shu. Pyrvinium Treatment Confers Hepatic Metabolic Benefits via β-Catenin Downregulation and AMPK Activation. Pharmaceutics 2021, 13 (3) , 330. https://doi.org/10.3390/pharmaceutics13030330
    11. Yi-Chuang Xu, Yi-Huan Xu, Tao Zhao, Li-Xiang Wu, Shui-Bo Yang, Zhi Luo. Waterborne Cu exposure increased lipid deposition and lipogenesis by affecting Wnt/β-catenin pathway and the β-catenin acetylation levels of grass carp Ctenopharyngodon idella. Environmental Pollution 2020, 263 , 114420. https://doi.org/10.1016/j.envpol.2020.114420
    12. Nazariy Pokhodylo, Yurii Slyvka, Volodymyr Pavlyuk. Synthesis, crystal structure and Hirshfeld surface analysis of N -(4-chlorophenyl)-5-cyclopropyl-1-(4-methoxyphenyl)-1 H -1,2,3-triazole-4-carboxamide. Acta Crystallographica Section E Crystallographic Communications 2020, 76 (5) , 756-760. https://doi.org/10.1107/S2056989020005848

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