9KNH

Structural complex of FTO bound with Dac590

This is a non-PDB format compatible entry.

Summary for 9KNH

• Entry DOI: 10.2210/pdb9knh/pdb
• Descriptor: Alpha-ketoglutarate-dependent dioxygenase FTO, 2-[[2-chloranyl-4-(3,5-dimethyl-1,2-oxazol-4-yl)-6-fluoranyl-phenyl]amino]-5-methoxy-benzoic acid, N-OXALYLGLYCINE, ... (4 entities in total)
• Functional Keywords: n6-methyladenosine(m6a) demethylase, inhibitor, complex, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 55527.69

Authors

Yang, C.G.,Yang, T. (deposition date: 2024-11-18, release date: 2025-09-03)

Primary citation

Yang, T.,Dong, Z.,Du, R.,Wang, Y.,Liu, L.,Xue, Y.,Zhang, X.,Liao, Y.,Gan, J.,Yu, X.,Huang, Y.,Yang, C.G.
Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy.
J.Med.Chem., 68:13714-13727, 2025

PubMed Abstract: N-Methyladenosine (mA), the most prevalent mRNA modification, undergoes dynamic regulation mediated by the demethylase fat mass and obesity-associated protein (FTO), which is aberrantly overexpressed in acute myeloid leukemia (AML) and drives leukemogenesis. Based on the structure-guided optimization of our previously reported FTO inhibitor and fluorescein, we developed , a tricyclic benzoic acid derivative with potent FTO inhibitory activity and improved pharmacokinetic properties. exerts a robust antiproliferative effect on AML cells by suppressing oncogenic FTO signaling. Oral administration of significantly inhibited xenograft tumor growth and prolonged survival in AML mouse models with no observed toxicity. Notably, synergized with decitabine to enhance DNA hypomethylation and further improve the survival rates. Our study identifies as a potent orally bioavailable FTO inhibitor and demonstrates a combinatorial strategy through dual epigenetic modulations for enhanced AML therapy.

PubMed: 40579742
DOI: 10.1021/acs.jmedchem.5c00566

Experimental method

X-RAY DIFFRACTION (2.9 Å)