A potential new drug for obesity

22 July 2014.Scientists in NUS have discovered the first subfamily-selective and cell-active FTO inhibitor which could pave the way for novel anti-obesity treatment.

Obesity is one of the world’s most pressing health problems. It not only predisposes the individual to serious conditions, such as type 2 diabetes and cardiovascular diseases, but also imposes a crushing burden on healthcare. Despite the urgent need to combat obesity, there is currently no safe and effective treatment for the disease. It is now clear that there is a genetic component to obesity. Recent landmark studies have identified a gene called FTO (fat mass and obesity-associated gene) to be strongly linked with obesity in both children and adults, and across major ethnic groups worldwide. Importantly, inhibition of FTO was found to protect from obesity, hence opening the exciting possibility of novel obesity treatment through small molecule inhibition of FTO.

A research team led by Prof Esther WOON from the Department of Pharmacy in NUS has now identified for the first time several subfamily-selective and potent inhibitors of FTO. This was achieved using an innovative drug discovery strategy called Dynamic Combinatorial Mass Spectrometric (DCMS), which combined the permutation power of Dynamic Combinatorial Chemistry with the sensitivity of ESI-Mass Spectrometric detection (see Figure). These inhibitors were found to be highly selective for FTO against other structurally related proteins and are active in cells, and show low cytotoxicity in cells. “This discovery could contribute significantly to the advancement in obesity research by enabling us to explore chemically the mechanistic and functional link between FTO and obesity, which would provide insights into the epigenetic causes of obesity,” says Esther. “Importantly, they could also form the basis for the development of novel anti-obesity drugs.” A patent application has been filed.

ewoon1

Image of Dynamic Combinatorial Mass Spectrometric (DCMS) approach to the discovery of FTO inhibitors. [Image credit: Esther WOON]

 

References

1. Demetriades M,  Leung IKH, Ratcliffe PJ, Woon ECY. Schofield CJ. "Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors."  Angewandte Chemie International Edition 51 (2012) 6672.

2. Woon ECY, Tumber A, Kawamura A. "Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases." Angewandte Chemie International Edition 51 (2012) 1631.

3. Woon ECY, Demetriades M, Bagg EAL. "Dynamic combinatorial mass spectrometry leads to inhibitors of a 2‑oxoglutarate dependent nucleic acid demethylase."Journal of the American Chemical Society 55 (2012) 2173.

4. Woon ECY, Sun L. "FTO inhibitors as therapeutic compounds." Patent pending (US Provisional Patent Application No. 1409405.6) Filed on 28 May 2014.