Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy
N<sup>6</sup>-Methyladenosine (m<sup>6</sup>A), 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 <b>Dac85</b> and fluorescein, we developed <b>Dac590</b>, a tricyclic benzoic acid derivative with potent FTO inhibitory activity and improved pharmacokinetic properties. <b>Dac590</b> exerts a robust antiproliferative effect on AML cells by suppressing oncogenic FTO signaling. Oral administration of <b>Dac590</b> significantly inhibited xenograft tumor growth and prolonged survival in AML mouse models with no observed toxicity. Notably, <b>Dac590</b> synergized with decitabine to enhance DNA hypomethylation and further improve the survival rates. Our study identifies <b>Dac590</b> as a potent orally bioavailable FTO inhibitor and demonstrates a combinatorial strategy through dual epigenetic modulations for enhanced AML therapy.
Authors
- Cai‐Guang Yang (ORCID: https://orcid.org/0000-0001-5778-4422)
- Lu Liu (ORCID: https://orcid.org/0000-0001-8865-3353)
- Ze Dong (ORCID: https://orcid.org/0000-0003-4876-415X)
- Jianhua Gan (ORCID: https://orcid.org/0000-0002-8438-8852)
- Yangyang Xue
- Teng Yang (ORCID: https://orcid.org/0000-0002-8617-4698)
- Yonggang Liao
- Rong Du (ORCID: https://orcid.org/0000-0002-1676-609X)
- Xi Zhang (ORCID: https://orcid.org/0000-0002-4638-3997)
- Yiqing Wang (ORCID: https://orcid.org/0000-0002-5626-8589)
- Yue Huang (ORCID: https://orcid.org/0009-0004-9139-8161)
- Xiaoxuan Yu (ORCID: https://orcid.org/0000-0002-6422-5159)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Shanghai Institute of Materia Medica (CN)
- Buchang Pharma (China) (CN)
- Advanced Research Institute (US)
- Institute for Advanced Study (DE)
- Pharmaceutical Biotechnology (Czechia) (CZ)
- University of Chinese Academy of Sciences (CN)
- State Key Laboratory of Pharmaceutical Biotechnology
- Nanjing University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00566
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China