Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy

Teng Yang; Ze Dong; Rong Du; Yiqing Wang; Lu Liu; Yangyang Xue; Xi Zhang; Yonggang Liao; Jianhua Gan; Xiaoxuan Yu; Yue Huang; Cai-Guang Yang

doi:10.1021/acs.jmedchem.5c00566

Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy

J Med Chem. 2025 Jun 27. doi: 10.1021/acs.jmedchem.5c00566. Online ahead of print.

Authors

Teng Yang^{1

2}, Ze Dong^{1

2}, Rong Du^{1

2

3}, Yiqing Wang^{1

2

3}, Lu Liu^{1

2}, Yangyang Xue⁴, Xi Zhang^{1

2

3

5}, Yonggang Liao⁶, Jianhua Gan⁷, Xiaoxuan Yu^{4

8}, Yue Huang^{1

2

3}, Cai-Guang Yang^{1

2

3

5}

Affiliations

¹ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
² University of the 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.
⁴ Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁵ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
⁶ Rname Pharmaceutical Technology (Shanghai) Co., LTD., Shanghai 430048, China.
⁷ School of Life Sciences, Fudan University, Shanghai 200433, China.
⁸ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.

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

Abstract

N⁶-Methyladenosine (m⁶A), 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 Dac85 and fluorescein, we developed Dac590, a tricyclic benzoic acid derivative with potent FTO inhibitory activity and improved pharmacokinetic properties. Dac590 exerts a robust antiproliferative effect on AML cells by suppressing oncogenic FTO signaling. Oral administration of Dac590 significantly inhibited xenograft tumor growth and prolonged survival in AML mouse models with no observed toxicity. Notably, Dac590 synergized with decitabine to enhance DNA hypomethylation and further improve the survival rates. Our study identifies Dac590 as a potent orally bioavailable FTO inhibitor and demonstrates a combinatorial strategy through dual epigenetic modulations for enhanced AML therapy.