Discovery of the 2,3-Dihydrobenzopyrane-4-one as a Potent FTO Inhibitor against Obesity-Related Metabolic Diseases
Year: 2025
Type: article
Abstract: 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 40, 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 via the FTO-FOXO1-G6PC/PCK1 axis and increasing adipose tissue heat production for weight loss via the FTO-FOXO1-Ucp1 axis in vivo . 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.
Source: Journal of Medicinal Chemistry
Authors: Duo Ma, Xianan Liu, Xianan Liu, Xingxing Zhang, Yaling Hong, Yumeng Wang, Famin Zhang, Leran Du, Junjie Zhao, Quan Wang, Cui Chang, Wenhu Liu, Yan Lou, Xinhua Liu, Xinhua Liu
Institutions: Anhui Medical University, University of Hong Kong
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Award: G3422679957
OpenAlex ID: W4408922697