Xanthine derivatives inhibit FTO in an L-ascorbic acid-dependent manner.

Xanthine derivatives were identified as inhibitors of the N6-methyladenosine (m6A) demethylase activity of fat-mass-and-obesity-associated protein (FTO) by activity-based high-throughput screening using the m6A-sensitive ribonuclease MazF. Pentoxifylline exhibited L-ascorbic acid concentration-dependent inhibitory activity against FTO, an unprecedented mode of inhibition, indicating that L-ascorbic acid is a promising key for designing FTO-specific inhibitors.