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 11b, which merges key fragments of
Hz (3) and MA (4), 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 11b decreased the viability of acute monocytic leukemia
cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are
FTO target genes. Thus, Hz (3)/MA (4) hybrid
analogues represent an entry into a new class of FTO-selective inhibitors.