Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.

Summary FTO, an mRNA N 6 -methyladenosine (m 6 A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTOinhibitors, namely FB23 and FB23-2, which directly bind to FTOand selectively inhibit FTO's m 6 A demethylaseactivity. Mimicking FTOdepletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro . Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cellsin xeno-transplanted mice. Collectively, our data suggest that FTOis a druggabletarget and that targeting FTOby small-molecule inhibitors holds potential to treat AML.