发现新型 mRNA 去甲基酶 FTO 抑制剂，用于食管癌治疗。

Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer.

机构信息

Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.

Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1995-2003. doi: 10.1080/14756366.2022.2098954.

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 exhibited the most robust inhibition of FTO with an IC 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 value of 2.17, 1.35, 0.95, 4.15, and 0.83 μM, respectively. In addition, arrested the cell cycle at G2 phase against TE-1 and EC109 cells in a concentration-dependent manner. Analysis of cellular mechanisms demonstrated that concentration-dependently regulated epithelial mesenchymal transition (EMT) pathway and PI3K/AKT pathway against TE-1 and EC109 cells. Molecular docking studies that formed important hydrogen-bond interaction with Lys107, Asn110, Tyr108, and Leu109 of FTO. These findings suggested that as a novel FTO inhibitor and orally antitumor agent deserves further investigation to treat esophageal cancer.

本研究合成了一系列作为新型脂肪量和肥胖相关蛋白（FTO）抑制剂的 1,2,3-三唑类似物。在所有的 1,2,3-三唑中，化合物对 FTO 的抑制作用最强，IC 值为 780nM。它对 KYSE-150、KYSE-270、TE-1、KYSE-510 和 EC109 细胞系显示出强大的抗增殖活性，IC 值分别为 2.17、1.35、0.95、4.15 和 0.83μM。此外，以浓度依赖的方式使 TE-1 和 EC109 细胞的细胞周期停滞在 G2 期。细胞机制分析表明，浓度依赖性地上调了 EMT 通路和 PI3K/AKT 通路，针对 TE-1 和 EC109 细胞。分子对接研究表明，与 FTO 的 Lys107、Asn110、Tyr108 和 Leu109 形成重要的氢键相互作用。这些发现表明，作为一种新型的 FTO 抑制剂和口服抗肿瘤药物，值得进一步研究用于治疗食管癌。