Obesity is currently one of the leading cause of premature death worldwide. Despite major therapeutic advances, there is currently no safe and effective drug for the long-term treatment of obesity. A series of recent, high-profile studies has identified FTO (fat mass and obesity-associated) gene to be strongly-linked with an increased risk of obesity in both children and adults, and in all major ethnic groups worldwide. Unlike other ‘obesity genes’ discovered previously, the FTO risk allele is highly prevalent across populations (14-52%). Importantly, inactivation of FTO protein was found to protect against diet-induced obesity in several animal studies. Hence, FTO inhibition may provide a novel, genetic-based approach to the treatment of obesity and related metabolic syndrome. FTO belongs to the AlkB family of nucleic acid demethylases. These enzymes share a high level of sequence and structural homology (&gt;60%), but have distinct physiological functions. In this presentation, we will describe the use of an innovative dynamic combinatorial chemistry (DCC)-based strategy, which led to the discovery of the first subfamily-selective and cell-active inhibitor of FTO CA (IC50 =0.81µM). CA not only demonstrates considerable (30 to 100-fold) selectivity for FTO over other AlkB subfamily members, but also discriminates against several other structurally-related oxygenases, such as PHD2 and JMJD2A. Such selectivity is rarely achieved for any enzyme family. The mechanism of FTO inhibition was subsequently analysed using kinetic, crystallographic and cell-based studies (Chemical Science,2015,6,112). Remarkably, treatment of human myotubes with CA dramatically reversed several of the metabolic impairments associated with obesity and diabetes, leading to significant improvement in mitochondrial oxidative function, fatty acid oxidation and basal glucose uptake (unpublished results). Similar metabolic benefits were also achieved with human adipocytes. These preclinical findings suggest that CA is a highly promising FTO lead, and FTO inhibition could be a viable therapeutic strategy for obesity and related metabolic diseases.

Discovery of the first subfamily-selective inhibitor of FTO for novel treatment of obesity and related metabolic syndrome

252nd National Meeting (2016)

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