Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer |
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| Authors: | Bo Qin Qian Bai Dan Yan Fanxiang Yin Zhu Zhu Chaoyuan Xia Yang Yang Yi Zhao |
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| Affiliation: | aTranslational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China;bDepartment of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China |
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| Abstract: | 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 IC50 value of 780 nM. It displayed the potent antiproliferative activity against KYSE-150, KYSE-270, TE-1, KYSE-510, and EC109 cell lines with IC50 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. |
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| Keywords: | FTO 1 2 3-triazole esophageal cancer cell cycle molecular docking |
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