Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy

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.