7WCV

Co-crystal structure of FTO bound to 6e

7WCV の概要

• エントリーDOI: 10.2210/pdb7wcv/pdb
• 分子名称: Alpha-ketoglutarate-dependent dioxygenase FTO, 2-OXOGLUTARIC ACID, MANGANESE (II) ION, ... (5 entities in total)
• 機能のキーワード: rna demethylase, rna binding protein, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57020.88

構造登録者

Yang, C.-G.,Gan, J.H. (登録日: 2021-12-20, 公開日: 2022-07-06, 最終更新日: 2023-11-29)

主引用文献

Liu, Z.,Duan, Z.,Zhang, D.,Xiao, P.,Zhang, T.,Xu, H.,Wang, C.H.,Rao, G.W.,Gan, J.,Huang, Y.,Yang, C.G.,Dong, Z.
Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors.
J.Med.Chem., 65:10638-10654, 2022

PubMed Abstract: The -methyladenosine (mA) demethylase FTO is overexpressed in acute myeloid leukemia (AML) cells and promotes leukemogenesis. We previously developed tricyclic benzoic acid FB23 as a highly potent FTO inhibitor in vitro. However, it showed a moderate antiproliferative effect on AML cells. In this work, we performed a structure-activity relationship study of tricyclic benzoic acids as FTO inhibitors. The analog exhibited excellent inhibitory effects on FTO similar to that of FB23 in vitro. In contrast to FB23, exerted a strong antiproliferative effect on AML cells. Like knock down, upregulated and expression and increased the protein abundance while it downregulated expression and decreased MYC protein abundance. These genes are key FTO targets in AML cells. Finally, treatment improved the survival rate of MONOMAC6-transplanted NSG mice. Collectively, our data suggest that targeting FTO with tricyclic benzoic acid inhibitors may be a potential strategy for treating AML.

PubMed: 35793358
DOI: 10.1021/acs.jmedchem.2c00848

実験手法

X-RAY DIFFRACTION (2.3 Å)