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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5

Yue Huang1, Jingli Yan2, Qi Li1

  • 1CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Nucleic Acids Research
|December 3, 2014
PubMed

Insights

Meclofenamic acid selectively inhibits the FTO enzyme, a key player in mRNA demethylation. This discovery offers new tools for studying FTO and developing targeted medical treatments.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Epigenetics

Background:

  • N(6)-methyladenosine (m(6)A) is a prevalent mRNA modification.
  • FTO and ALKBH5 are human demethylases that remove m(6)A.
  • Selective inhibition of FTO over ALKBH5 is a significant challenge.

Purpose of the Study:

  • To identify a selective inhibitor of the FTO enzyme.
  • To elucidate the mechanism of FTO inhibition.
  • To explore the therapeutic potential of FTO inhibitors.

Main Methods:

  • Screening for FTO inhibitors.
  • Mechanistic studies of inhibitor binding.
  • Structural analysis of FTO/inhibitor complex.
  • Cell-based assays to assess m(6)A levels.

Main Results:

  • Meclofenamic acid (MA) identified as a potent and selective FTO inhibitor.
  • MA competes with m(6)A-containing nucleic acids for FTO binding.
  • Structural insights into FTO inhibition and selectivity.
  • MA treatment increases m(6)A levels in mRNA in HeLa cells.

Conclusions:

  • Meclofenamic acid is a valuable chemical probe for FTO.
  • Understanding FTO inhibition principles aids in designing future therapeutics.
  • Selective FTO inhibition has potential applications in medicine.

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