Discovery of the 2,3-Dihydrobenzopyrane-4-one as a Potent FTO Inhibitor against Obesity-Related Metabolic Diseases

The involvement of the fat mass and obesity-associated gene (FTO) in the development and advancement of metabolic disorders is widely recognized. However, the existing FTO inhibitor entacapone has been limited in clinical application due to its low potency and short plasma elimination half-life. Here, through drug library screening and in depth structure-activity relationship analysis, title compound <b>40</b>, eriodictyol was identified as a potent FTO inhibitor, and showed good binding to FTO by surface plasmon resonance (SPR) and Microscale thermophoresis (MST) detection. The residues Arg96, Tyr108, Ser229, Asp233, and Glu234 of FTO are essential for binding. Meanwhile, eriodictyol attenuated obesity-related metabolic diseases by enhancing glucose metabolism pathways <i>via</i> the FTO-FOXO1-G6PC/PCK1 axis and increasing adipose tissue heat production for weight loss <i>via</i> the FTO-FOXO1-Ucp1 axis <i>in vivo</i>. Surprisingly, eriodictyol showed good pharmacokinetic properties and no obvious toxicity. These results could provide the reference for design of new FTO inhibitors against obesity-related metabolic diseases.