Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Fat mass and obesity-associated protein (FTO) is an Fe(II) and 2-oxoglutarate (2OG)-dependent nucleic acid demethylase.
• FTO plays a role in the demethylation of N6-methyladenosine (m6A) in mRNA and is a potential anti-cancer target.

Purpose of the Study:

• To design and synthesize novel FTO inhibitors using structure-based drug design.
• To evaluate the potency and selectivity of synthesized inhibitors against FTO and related enzymes.

Main Methods:

• Utilized crystal structures of FTO with 2OG and substrate mimics for inhibitor design.
• Synthesized two series of FTO inhibitors.
• Characterized inhibitors using turnover and binding assays.
• Determined crystal structures of FTO and AlkB in complex with inhibitors.

Main Results:

• Identified a potent FTO inhibitor with binding interactions across the 2OG and substrate sites.
• Demonstrated selectivity of the inhibitor over other 2OG oxygenases, including PHD2, FIH, and KDMs.
• X-ray crystallography provided insights into inhibitor binding modes.

Conclusions:

• Structure-based design is effective for developing potent and selective 2OG oxygenase inhibitors.
• The identified FTO inhibitor holds potential for in vivo therapeutic applications in cancer treatment.