9KNI

Structural complex of FTO bound with 12j

This is a non-PDB format compatible entry.

Summary for 9KNI

• Entry DOI: 10.2210/pdb9kni/pdb
• Descriptor: Alpha-ketoglutarate-dependent dioxygenase FTO, 2-OXOGLUTARIC ACID, 3-[[2,6-bis(chloranyl)-4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]amino]thiophene-2-carboxylic acid, ... (4 entities in total)
• Functional Keywords: m6a eraser, fto inhibitor, complex, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 55462.33

Authors

Yang, C.G.,Gan, J.H. (deposition date: 2024-11-19, release date: 2025-03-12)

Primary citation

Zhang, D.,Liu, L.,Li, M.,Hu, X.,Zhang, X.,Xia, W.,Wang, Z.,Song, X.,Huang, Y.,Dong, Z.,Yang, C.G.
Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities.
Eur.J.Med.Chem., 289:117444-117444, 2025

PubMed Abstract: Fat mass and obesity-associated protein (FTO) is the first discovered RNA N-methyladenosine (mA) demethylase. The highly expressed FTO protein is required to trigger oncogenic pathways in acute myeloid leukemia (AML), which makes FTO a promising antileukemia drug target. In this study, we identify 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors with good antileukemia activity. We replaced the phenyl A-ring in FB23, the first-generation of FTO inhibitor, with five-membered heterocycles and synthesized a new class of FTO inhibitors. Compound 12o/F97 shows strong enzymatic inhibitory activity and potent antiproliferative activity. 12o/F97 selectively inhibits mA demethylation by FTO rather than ALKBH5, and has minimal effect on mA demethylation by ALKBH3. Additionally, 12o/F97 increases the protein levels of RARA and ASB2, while decreasing that of MYC in AML cell lines. Lastly, 12o/F97 exhibits antileukemia activity in a xenograft mice model without significant side-effects. The identification of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors not only expands the chemical space but also holds potential for antileukemia drug development.

PubMed: 40022879
DOI: 10.1016/j.ejmech.2025.117444

Experimental method

X-RAY DIFFRACTION (2.63 Å)