Structural basis for inhibition of the fat mass and obesity associated protein (FTO)

WeiShen Aik, Marina Demetriades, Muhammad K. K. Hamdan, Eleanor A. L. Bagg, Kar Kheng Yeoh, Clarisse Lejeune, Zhihong Zhang, Michael A. McDonough*, Christopher J. Schofield*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

130 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3680-3688
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number9
Early online date23 Apr 2013
DOIs
Publication statusPublished - May 2013

Scopus Subject Areas

  • Molecular Medicine
  • Drug Discovery

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