9VG4

Structural complex of FTO bound with 8j

This is a non-PDB format compatible entry.

Summary for 9VG4

• Entry DOI: 10.2210/pdb9vg4/pdb
• Descriptor: Alpha-ketoglutarate-dependent dioxygenase FTO, 2-[[2-chloranyl-6-ethyl-4-[2-[[(E)-4-oxidanyl-4-oxidanylidene-but-2-enoyl]amino]ethylcarbamoyl]phenyl]amino]benzoic acid, N-OXALYLGLYCINE, ... (5 entities in total)
• Functional Keywords: fto, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 55299.40

Authors

Yang, C.G.,Gan, J.H. (deposition date: 2025-06-12, release date: 2025-11-05, Last modification date: 2026-05-27)

Primary citation

Zhang, X.,Wang, Z.,Xie, X.,Liu, G.,Dong, Z.,Yang, C.G.
Structure-Based Design of a Highly Potent Dual-Competitive FTO Inhibitor for Targeted m 6 A Demethylase Inhibition in AML.
J.Med.Chem., 68:22779-22798, 2025

PubMed Abstract: Fat mass and obesity-associated protein (FTO), an Fe/2-oxoglutarate ()-dependent RNA demethylase, removes -methyladenosine (mA) modification. FTO is overexpressed in AML, promoting pathogenesis through c-Myc upregulation. Using fragment linking of meclofenamic acid () and mimetics, we developed , a substrate/ dual-competitive FTO inhibitor. substantially inhibits FTO demethylation, exceeding its constituent fragments' activity, with high selectivity over ALKBH3 and ALKBH5. competition assay and docking confirm simultaneous occupation of substrate and pockets, although the cocrystal structure revealed a different binding site. To circumvent the limitation of poor cellular permeability of , we synthesized the prodrug ester , which suppressed AML cell viability, reduced mA levels, downregulated c-Myc and CEBPA, and upregulated ASB2 and RARA. It has also shown obvious tumor-inhibiting efficacy at the animal level. represents a highly potent FTO inhibitor with therapeutic potential, providing a framework for future development.

PubMed: 41190354
DOI: 10.1021/acs.jmedchem.5c01738

Experimental method

X-RAY DIFFRACTION (2.3 Å)