Identification of Natural Compound Radicicol as a Potent FTO Inhibitor

• Published in: Molecular pharmaceutics 2018-09, Vol.15 (9), p.4092-4098
• Main Authors: Wang, Ruiyong, Han, Zhifu, Liu, Bingjie, Zhou, Bin, Wang, Ning, Jiang, Qingwei, Qiao, Yan, Song, Chuanjun, Chai, Jijie, Chang, Junbiao
• Format: Article
• Language: English
• Subjects: Alpha-Ketoglutarate-Dependent Dioxygenase FTO - antagonists & inhibitors; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - chemistry; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism; Calorimetry; Crystallography, X-Ray; Humans; Macrolides - chemistry; Macrolides - pharmacology; Magnetic Resonance Spectroscopy; Models, Molecular
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.8b00522

The fat mass and obesity-associated protein (FTO), as an m6A demethylase, is involved in many human diseases. Virtual screening and similarity search in combination with bioactivity assay lead to the identification of the natural compound radicicol as a potent FTO inhibitor, which exhibits a dose-dependent inhibition of FTO demethylation activity with an IC50 value of 16.04 μM. Further ITC experiments show that the binding between radicicol and FTO was mainly entropy-driven. Crystal structure analysis reveals that radicicol adopts an L-shaped conformation in the FTO binding site and occupies the same position as N-CDPCB, a previously identified small molecular inhibitor of FTO. Unexpectedly, however, the 1,3-diol group conserved in radicicol and N-CDPCB assumes strikingly different orientations for interaction with FTO. The identification of radicicol as an FTO inhibitor and revelation of its recognition mechanism not only opens the possibility of developing new therapeutic strategies for treatment of leukemia but also provide clues for elucidation of the acting mechanisms of radicicol, which is a possible clinical candidate worth in-depth study.