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

  • Eur J Med Chem. 2025 Feb 25:289:117444. doi: 10.1016/j.ejmech.2025.117444.
Deyan Zhang  1 ,  Lu Liu  2 ,  Ming Li  1 ,  Xinyi Hu  1 ,  Xi Zhang  1 ,  Wenyang Xia  3 ,  Zhen Wang  2 ,  Xiaomin Song  2 ,  Yue Huang  4 ,  Ze Dong  5 ,  Cai-Guang Yang  6
Affiliations
  • 1. 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.
  • 2. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3. 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.
  • 4. 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. Electronic address: [email protected].
  • 5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
  • 6. 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; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. Electronic address: [email protected].
PMID: 40022879 DOI: 10.1016/j.ejmech.2025.117444
Abstract

Fat mass and obesity-associated protein (FTO) is the first discovered RNA N6-methyladenosine (m6A) 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 m6A demethylation by FTO rather than ALKBH5, and has minimal effect on m1A 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.

Keywords
Antileukemia; Demethylase FTO; N(6)-methyladenosine; RNA modification; Structure-activity relationship.
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