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.