Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer

A series of 1,2,3-triazole analogues as novel fat mass and obesity-associated protein (FTO) inhibitors were synthesised in this study. Among all 1,2,3-triazoles, compound C6 exhibited the most robust inhibition of FTO with an IC 50 value of 780 nM. It displayed the potent antiproliferative activity...

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Published in:Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.1995-2003
Main Authors: Qin, Bo, Bai, Qian, Yan, Dan, Yin, Fanxiang, Zhu, Zhu, Xia, Chaoyuan, Yang, Yang, Zhao, Yi
Format: Article
Language:English
Subjects:
1,2,3-triazole
1-Phosphatidylinositol 3-kinase
AKT protein
Body fat
Cell cycle
Esophageal cancer
FTO
G2 phase
Mesenchyme
molecular docking
mRNA
Research Paper
Triazoles
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Summary:A series of 1,2,3-triazole analogues as novel fat mass and obesity-associated protein (FTO) inhibitors were synthesised in this study. Among all 1,2,3-triazoles, compound C6 exhibited the most robust inhibition of FTO with an IC 50 value of 780 nM. It displayed the potent antiproliferative activity against KYSE-150, KYSE-270, TE-1, KYSE-510, and EC109 cell lines with IC 50 value of 2.17, 1.35, 0.95, 4.15, and 0.83 μM, respectively. In addition, C6 arrested the cell cycle at G2 phase against TE-1 and EC109 cells in a concentration-dependent manner. Analysis of cellular mechanisms demonstrated that C6 concentration-dependently regulated epithelial mesenchymal transition (EMT) pathway and PI3K/AKT pathway against TE-1 and EC109 cells. Molecular docking studies that C6 formed important hydrogen-bond interaction with Lys107, Asn110, Tyr108, and Leu109 of FTO. These findings suggested that C6 as a novel FTO inhibitor and orally antitumor agent deserves further investigation to treat esophageal cancer.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2022.2098954