A Novel Inhibitor of the Obesity-Related Protein FTO

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The fat mass and obesity associated protein (FTO) plays a crucial role in regulating mRNA splicing and adipogenesis through demethylation of m exto extsuperscript{6}A.
• FTO-mediated demethylation is dependent on Fe(II) and α-ketoglutarate.
• Developing specific FTO inhibitors is essential for investigating FTO biology and identifying therapeutic targets for obesity and related diseases.

Purpose of the Study:

• To identify novel small molecules that inhibit FTO activity.
• To characterize the interaction between a newly identified inhibitor and FTO.
• To provide a basis for developing more potent and selective FTO inhibitors.

Main Methods:

• Small molecule screening to identify FTO inhibitors.
• Biochemical assays to confirm FTO inhibition.
• X-ray crystallography to determine the complex structure of FTO with the inhibitor.

Main Results:

• Identification of 4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol (CHTB) as a novel FTO inhibitor.
• Elucidation of the crystal structure of CHTB complexed with human FTO.
• Demonstration of a specific binding mode of CHTB to FTO.

Conclusions:

• CHTB is a novel small molecule inhibitor of FTO.
• The specific binding of CHTB to FTO provides structural insights.
• This finding opens avenues for the development of advanced FTO inhibitors for therapeutic applications in obesity.