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Structural Basis for Inhibition of the Fat Mass and Obesity Associated Protein (FTO)

DOI: 10.1021/jm400193d DOI Help
PMID: 23547775 PMID Help

Authors: Weishen Aik (University of Oxford) , Marina Demetriades (University of Oxford) , Muhammad Khairul Kamilin Hamdan (University of Oxford) , Eleanor Bagg (University of Oxford) , Kar Kheng Yeoh (University of Oxford) , Clarisse Lejeune (University of Oxford) , Zhihong Zhang (University of Oxford) , Michael Mcdonough (Department of Chemistry, University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56 (9)

State: Published (Approved)
Published: April 2013

Abstract: The fat mass and obesity associated protein (FTO) is a potential target for anti-obesity medicines. FTO is a 2-oxoglutarate (2OG)-dependent N-methyl nucleic acid demethylase that acts on substrates including 3-methylthymidine, 3-methyluracil, and 6-methyladenine. To identify FTO inhibitors, we screened a set of 2OG analogues and related compounds using differential scanning fluorometry- and liquid chromatography-based assays. The results revealed sets of both cyclic and acyclic 2OG analogues that are FTO inhibitors. Identified inhibitors include small molecules that have been used in clinical studies for the inhibition of other 2OG oxygenases. Crystallographic analyses reveal inhibition by 2OG cosubstrate or primary substrate competitors as well as compounds that bind across both cosubstrate and primary substrate binding sites. The results will aid the development of more potent and selective FTO inhibitors.

Journal Keywords: Drug; Humans; Models; Molecular; Protein; Proteins; Substrate Specificity

Subject Areas: Medicine, Chemistry

Instruments: I03-Macromolecular Crystallography