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

WeiShen Aik1, Marina Demetriades, Muhammad K K Hamdan

  • 1Chemistry Research Laboratory, University of Oxford , 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.

Journal of Medicinal Chemistry
|April 4, 2013
PubMed

Insights

Researchers identified novel inhibitors for the fat mass and obesity associated protein (FTO), a key target for anti-obesity drugs. These compounds, including 2-oxoglutarate (2OG) analogues, show promise for developing more effective obesity treatments.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • The fat mass and obesity associated protein (FTO) is a crucial N-methyl nucleic acid demethylase.
  • FTO is recognized as a significant therapeutic target for developing anti-obesity medications.

Purpose of the Study:

  • To identify novel inhibitors of the FTO enzyme.
  • To explore 2-oxoglutarate (2OG) analogues and related compounds as potential FTO inhibitors.

Main Methods:

  • Screening of 2OG analogues and related compounds using differential scanning fluorometry and liquid chromatography-based assays.
  • Inhibitor characterization through crystallographic analyses to determine binding modes.

Main Results:

  • Identification of both cyclic and acyclic 2OG analogues that inhibit FTO activity.
  • Discovery of small molecules, some previously used in clinical studies for other 2OG oxygenases, that inhibit FTO.
  • Crystallographic data revealed distinct binding mechanisms, including competition for cosubstrate/substrate sites and dual-site binding.

Conclusions:

  • The identified 2OG analogues represent promising scaffolds for the development of FTO inhibitors.
  • These findings provide a foundation for designing more potent and selective FTO inhibitors for anti-obesity drug discovery.

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