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

ABSTRACT: 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

SUBMITTER: Shishodia S 

PROVIDER: S-EPMC8631710 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature