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Researchers identify several potent inhibitors of FTO gene

FTO-specific inhibitors could pave the way for the development of novel anti-obesity drugs and treatments

Individuals who are genetically predisposed to obesity may soon have a therapeutic solution to combat their condition, according researchers led by scientists from the National University of Singapore (NUS). They have identified several potent inhibitors that selectively target FTO (a fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO), these FTO-specific inhibitors pave the way for the development of novel anti-obesity drugs and treatments.

The research, led by Assistant Professor Esther Woon from the Department of Pharmacy at the NUS Faculty of Science, along with colleagues from the Institute of Molecular and Cell Biology (IMCB) at the Agency for Science, Technology and Research (A*STAR), as well as the Nanyang Technological University, is the first to look at potential treatment of obesity from a genetic perspective. The findings 'A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO', were published online in the journal Chemical Science.

Among the genetic influences, the FTO gene is one that is strongly linked to obesity, with genome wide studies showing that people with certain variations of the FTO gene are 70 per cent more likely to become obese. This has been shown for both children and adults, as well as across all major ethnic groups, including Chinese, Malay and Indian populations in Singapore.

To address this huge therapeutic gap in medicine, and to explore whether FTO is a probable therapeutic target for obesity, the researchers started to look at developing specific inhibitors of the FTO protein.

The researchers discovered several novel and potent FTO inhibitors, with the strongest being the 4-[N'-(4-Benzyl-pyridine-3-carbonyl)-hydrazino]-4-oxo-but-2-enoic acid. Many of the inhibitors are also able to selectively target FTO over other proteins that are very similar structurally. This discovery was done through an innovative drug discovery strategy called Dynamic Combinatorial Mass-Spectrometry, a method which combines the permutation power of dynamic combinatorial chemistry and the sensitivity of protein mass-spectrometry.

"Such remarkable selectivity is rarely achieved and is the 'holy grail' in drug discovery, as it potentially translates to significantly reduced side effects,” said Woon. “This is demonstrated by the promising activities and low cytotoxicity of some of these inhibitors in cells."

The researchers claim their findings could reveal new areas for the development of novel anti-obesity drugs and treatments. They are currently working closely with Associate Professor Tai E Shyong and Assistant Professor Sue-Anne Toh, who are from NUS Yong Loo Lin School of Medicine, as well as Dr Liu Mei Hui of the Food Science and Technology programme at the NUS Faculty of Science, to study the molecular mechanisms and effects of the FTO inhibitors on other closely-related metabolic diseases, such as diabetes. They also hope to secure funding to further their research.

"Recognising a genetic, or even epigenetic, component in obesity certainly changes the way in which we approach to the treatment of the disease. What is so exciting about these FTO inhibitors is that they represent a potential new class of anti-obesity drugs, which target one of the most common genetic causes of obesity," she added. "Conceivably, if this research comes to fruition, it should benefit a large majority of the population. However, there is still a lot to learn about the actual mechanistic link between FTO and obesity. The challenge now is to uncover the mystery through the use of these selective FTO inhibitors.”

The researchers have filed a patent for the inhibitors through the NUS Industry Liaison Office, which is part of NUS Enterprise.

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