Structure–Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors

The N6-methyladenosine (m6A) demethylase FTO is overexpressed in acute myeloid leukemia
(AML)
cells and promotes leukemogenesis. We previously developed tricyclic
benzoic acid FB23 as a highly potent FTO inhibitor in vitro. However,
it showed a moderate antiproliferative effect on AML cells. In this
work, we performed a structure–activity relationship study
of tricyclic benzoic acids as FTO inhibitors. The analog 13a exhibited excellent inhibitory effects on FTO similar to that of
FB23 in vitro. In contrast to FB23, 13a exerted a strong
antiproliferative effect on AML cells. Like FTO knock
down, 13a upregulated ASB2 and RARA expression and increased the protein abundance while
it downregulated MYC expression and decreased MYC
protein abundance. These genes are key FTO targets in AML cells. Finally, 13a treatment improved the survival rate of MONOMAC6-transplanted
NSG mice. Collectively, our data suggest that targeting FTO with tricyclic
benzoic acid inhibitors may be a potential strategy for treating AML.