Structure-based Discovery of a Non-competitive FTO Inhibitor Bound to a Cryptic Site at the Domain Interface
Aayushi Singh1, Francesco Pettini2, Beatrice Gianibbi3
1Department of Chemistry, Iowa State University, Ames, IA, USA.
Journal of Molecular Biology
|December 7, 2025
Summary
Researchers discovered a novel molecular scaffold that selectively inhibits the fat mass and obesity-associated (FTO) protein. This allosteric inhibitor targets a cryptic site, offering a new strategy for treating metabolic diseases and cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The fat mass and obesity-associated (FTO) protein is implicated in obesity, type 2 diabetes, Alzheimer's, and cancer.
- Current FTO inhibitors are competitive and face challenges in achieving subfamily selectivity.
- Developing selective FTO inhibitors is crucial for pharmaceutical research.
Purpose of the Study:
- To discover a novel molecular scaffold for selective FTO inhibition.
- To characterize the binding mode and inhibitory mechanism of the new scaffold.
- To explore a new therapeutic strategy for FTO-related diseases.
Main Methods:
- High-throughput virtual screening of FTO cryptic pockets.
- Solution Nuclear Magnetic Resonance (NMR) spectroscopy.
- Molecular dynamics simulations and enzyme kinetic assays.
Main Results:
- Identified a molecular scaffold that binds to a cryptic site between FTO structural domains.
- Demonstrated non-competitive inhibition by perturbing substrate binding.
- Confirmed FTO's unique multi-domain structure among AlkB family members.
Conclusions:
- The discovered molecule represents a novel allosteric inhibitor scaffold for FTO.
- This approach offers a promising avenue for developing highly selective FTO inhibitors.
- Further development could lead to improved therapeutic strategies for metabolic diseases and cancer.
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