Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer. (31st December 2022)

• Record Type: Journal Article
• Authors: Qin, Bo; Bai, Qian; Yan, Dan; Yin, Fanxiang; Zhu, Zhu; Xia, Chaoyuan; Yang, Yang; Zhao, Yi
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 37:Number 1(2022)
• Page Start: 1995
• Page End: 2003
• Publication Date: 2022-12-31
• Subjects: FTO -- 1, 2, 3-triazole -- esophageal cancer -- cell cycle -- molecular docking; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2098954
• Languages: English
• ISSNs: 1475-6366

Abstract

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. GRAPHICAL ABSTRACT: UF0001