Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors

FTO catalyzes the
Fe­(II) and 2-oxoglutarate (2OG)-dependent modification
of nucleic acids, including the demethylation of N6-methyladenosine (m6A) in mRNA. FTO is a proposed
target for anti-cancer therapy. Using information from crystal structures
of FTO in complex with 2OG and substrate mimics, we designed and synthesized
two series of FTO inhibitors, which were characterized by turnover
and binding assays, and by X-ray crystallography with FTO and the
related bacterial enzyme AlkB. A potent inhibitor employing binding
interactions spanning the FTO 2OG and substrate binding sites was
identified. Selectivity over other clinically targeted 2OG oxygenases
was demonstrated, including with respect to the hypoxia-inducible
factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected
JmjC histone demethylases (KDMs). The results illustrate how structure-based
design can enable the identification of potent and selective 2OG oxygenase
inhibitors and will be useful for the development of FTO inhibitors
for use in vivo.