Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and 
ALKBH5, oxidatively demethylate abundant N(6)-methyladenosine (m(6)A) residues 
in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains 
a challenge, however. Here, we have identified meclofenamic acid (MA) as a 
highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug 
that mechanistic studies indicate competes with FTO binding for the 
m(6)A-containing nucleic acid. The structure of FTO/MA has revealed much about 
the inhibitory function of FTO. Our newfound understanding, revealed herein, of 
the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped 
elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of 
HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of 
m(6)A modification in mRNA. Our collective results highlight the development of 
functional probes of the FTO enzyme that will (i) enable future biological 
studies and (ii) pave the way for the rational design of potent and specific 
inhibitors of FTO for use in medicine.