Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach.

Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound , which merges key fragments of Hz () and MA (), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate -methyladenosine in mRNA, and induced upregulation of and downregulation of , which are FTO target genes. Thus, Hz ()/MA () hybrid analogues represent an entry into a new class of FTO-selective inhibitors.