Mutations of the FTO (Fat Mass and Obesity) gene has recently been identified, through genome-wide association studies, to be associated with obesity in both children and adults, and across multiple ethnic groups.1 In addition, inactivation of FTO is found to protect from obesity; this is important given that obesity predisposes individuals to serious chronic conditions, such as diabetes, cardiovascular disease, hypertension and certain cancers and is the leading cause of premature death worldwide. FTO belongs to the AlkB family of enzymes, which includes AlkB and ALKBH1-8. There is increasing evidence that the nucleic acid demethylase activity of FTO may regulate metabolic processes through epigenetic mechanism.
To date, there is no report of inhibitor of FTO; however we have demonstrated that AlkB, and by implication the structurally related FTO, are amenable to potent inhibition by small molecules.2 We have subsequently identified, for the first time, subfamily-selective and cell-active inhibitor of FTO.3 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 (Figure 1).4-6 A patent application has been filed.7
These inhibitors were found to be highly selective for FTO against other structurally related proteins and are active in cells, with low cytotoxicity (Figure 2). Work is currently underway to apply these probes for mechanistic and functional studies in various human tissues. This discovery could contribute significantly to the advancement in obesity research by enabling us to explore chemically the epigenetic link between FTO and obesity. Importantly, they could also form the basis for the development of novel anti-obesity drugs.
- Frayling, T. M. et. al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316, 889-894.
- Woon, E. C. Y.; Demetriades, M.; Bagg, E. A. L. et. al. Dynamic combinatorial mass spectrometry leads to inhibitors of a 2‑oxoglutarate dependent nucleic acid demethylase. Journal of Medicinal Chemistry 2012, 55, 2173-2184.
- Toh, J. D. W.; Sun, L.; Lau, L. Z. M.; Tan, J.; Low, J. J. A.; Tang, C. W. Q.; Cheong, E. J. Y.; Tan, M. J. H.; Chen, Y.; Hong, W.; Gao, Y-G., Woon. E. C. Y. A Strategy Based on Nucleotide Specificity Leads to Selective Inhibition of N6-Methyladenosine Demethylase FTO. Chemical Science, 2015, 6, 112-122.
- Demetriades, M.; Leung, I. K. H.; Ratcliffe, P. J.; Woon, E. C. Y.;* Schofield, C. J.* Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors. Angewandte Chemie International Edition 2012, 51, 6672-6675.
- Woon, E. C. Y.; Tumber, A.; Kawamura, A.; et. al. Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases. Angewandte Chemie International Edition 2012, 51, 1631-1634.
- Rose, N. R.; Woon, E. C. Y.; Kingham, G. L.; King, O. N. F.; et.al. Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. Journal of Medicinal Chemistry 2010, 53, 1810‑1818.
- Woon, E. C. Y.; Sun, L. FTO inhibitors as therapeutic compounds. Patent pending (US Provisional Patent Application No. 1409405.6) Filed on 28 May 2014.