1 research outputs found
Development of Cell-Active <i>N</i><sup>6</sup>‑Methyladenosine RNA Demethylase FTO Inhibitor
The direct nucleic acid repair dioxygenase FTO is an
enzyme that
demethylates <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) residues in mRNA <i>in vitro</i> and inside cells.
FTO is the first RNA demethylase discovered that also serves a major
regulatory function in mammals. Together with structure-based virtual
screening and biochemical analyses, we report the first identification
of several small-molecule inhibitors of human FTO demethylase. The
most potent compound, the natural product rhein, which is neither
a structural mimic of 2-oxoglutarate nor a chelator of metal ion,
competitively binds to the FTO active site <i>in vitro</i>. Rhein also exhibits good inhibitory activity on m<sup>6</sup>A
demethylation inside cells. These studies shed light on the development
of powerful probes and new therapies for use in RNA biology and drug
discovery