9KNI | pdb_00009kni

Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities.

(2025) Eur J Med Chem 289: 117444-117444

• PubMed: 40022879 Search on PubMed
• DOI: https://doi.org/10.1016/j.ejmech.2025.117444
• Primary Citation of Related Structures:  
  9KNI


• PubMed Abstract: 
  

  Fat mass and obesity-associated protein (FTO) is the first discovered RNA N ⁶ -methyladenosine (m ⁶ A) 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 m ⁶ A demethylation by FTO rather than ALKBH5, and has minimal effect on m ¹ A 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.

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Organizational Affiliation: 

School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.