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

Abstract

The <i>N</i>⁶-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 <b>13a</b> exhibited excellent inhibitory effects on FTO similar to that of FB23 in vitro. In contrast to FB23, <b>13a</b> exerted a strong antiproliferative effect on AML cells. Like <i>FTO</i> knock down, <b>13a</b> upregulated <i>ASB2</i> and <i>RARA</i> expression and increased the protein abundance while it downregulated <i>MYC</i> expression and decreased MYC protein abundance. These genes are key FTO targets in AML cells. Finally, <b>13a</b> 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.