Scientific Merit and Feasibility of Fructokinase Inhibiton for Obesity

DESCRIPTION provided by applicant Intake of added sweeteners high fructose corn syrup and sucrose independently predicts the development of obesity metabolic syndrome and diabetes Despite recommendations by WHO and the AHA to reduce sugar intake to to percent of total energy intake the mean intake of added sugars remains percent of the diet and percent of the population ingest more than of their diet as added sugars While public health interventions may help reduce sugar intake the addicting properties of sugar coupled with its ubiquitous presence in processed foods makes this a laudable challenge Our group has focused on the biology by which sugar induces obesity and metabolic syndrome We have identified fructokinase C as the key enzyme driving sugar associated metabolic disorders It is the ideal therapeutic target as fructokinase is specific for fructose metabolism and because people and mice lacking fructokinase are asymptomatic with normal lifespans Moreover mice lacking fructokinase are protected from developing obesity or insulin resistance in response to fructose and while they appear to still like sugar they ingest less sugar than normal mice suggesting that blocking fructokinase may help individuals reduce their sugar intake as opposed to the reverse To date there is no drug available to block sugar induced metabolic disorders or to block sugar craving so developing a fructokinase inhibitor would be novel and significant As such Colorado Research Partners LLC CRP has initiated a drug development program We have screened botanicals using a high throughput enzymatic assay and identified andgt purified compounds that inhibit KHK C with IC s ranging from to M We have also been able to show that some of these compounds are effective inhibitors in both cell culture and in vivo in the rat and mouse We have further performed computer modeling Schr dinger software of these compounds with the crystal structure of fructokinase C to evaluate binding energies and have identified different scaffolds that can be synthetically modified using a smart drug design approach Using structure based drug design SBDD and pharmacophore modeling virtual screening we have identified over derivatives with superior binding energies compared to the original prototypes We have also assembled a team of chemists and biologists that will allow us to chemically prepare and test new chemical entities NCEs for inhibitory activity to fructokinase in cell free systems in cell culture and in animal models We
now propose for this Phase I to generate NCEs based on these scaffolds that are active in the sub micromolar andlt nM range Our goal milestone is to develop at least distinct compounds that are active in cell culture and in vivo proof of mechanism in a rodent model and that is specific for fructokinase compared to other sugar kinases potency Our goal at the end of phase I is to have several lead compounds that are ready for more detailed studies including pharmacokinetics efficacy in long term models of sugar induced obesity and metabolic syndrome and for intensive toxicology studies We believe that the development of the first in a class of drug molecules to block sugar based metabolism will represent a major breakthrough in the battle against obesity and diabetes

PUBLIC HEALTH RELEVANCE Sugar makes up percent of the average diet and is strongly associated with the development of obesity and diabetes yet no specific drug exists to block the metabolic effects of sugar We have identified fructokinase as the key enzyme driving sugar metabolic effects and have identified several promising chemical scaffolds with inhibitory activity The goal of this Phase I study is to develop new lead chemical entities with activity i the nanomolar range that are specific and have in vivo efficacy and which can be further developed as lead compounds for future development as the first drugs to block sugar induced metabolic disorders