Scientific Merit and Feasibility of Fructokinase Inhibition for Obesity

Our goal is to develop a firstin class therapeutic agent that directly blocks the metabolism of fructosea key component in sugarIntake of sugarsucroseand high fructose corn syrupHFCSinduces metabolic syndrome and diabetes in laboratory animals and are strongly associated with obesity and diabetes in humansBoth sucrose and HFCS contain fructosewhich stimulates food intake by inducing leptin resistance while lowering metabolismincluding blocking fatty acid oxidationWe found that these effects of fructose were mediated by the unique ability of fructose to decrease intracellular ATP levels during its metabolismwhich is due to the rapid consumption of ATP by the enzyme fructokinase CKHK Cin the liverMice lacking KHK C are protected from sugar induced obesityfatty liverand metabolic syndromeWhile sugar and HFCS are major sources of dietary fructosewe found that fructose can be endogenously produced by high glycemic or high salt diets and that blocking fructokinase protects animals from obesity and insulin resistance from this source of fructoseFurthermoremice lacking fructokinase are also protected from the orphan diseasehereditary fructose intoleranceHFIBlocking KHK C is safeas humans lacking have a normal life span and mice lacking KHK C are even protected from aging associated kidney diseaseIn Phase I of our STTRour goal was to develop two novel lead compounds with ICvalues in the submicromolar range that were effective at blocking KHK C both in vitro and in vivo and with specificity for KHK compared to other sugar kinasesWhile much of our initial effort was aimed at developing derivatives of a nutraceuticalostholas novel chemical entitieswe were unable to break the submicromolar ICtargetHowevermore recently a series of novel indazole compounds has been identifiedwhich have high potency and selectivityand have robust in vivo activity after oral administrationIn this Phase II proposalwe plan to optimize our lead inhibitors using structure based drug designSBDDAimis to optimize our lead inhibitors with increased potencyICandltnMand selectivity guided by SBDDIn Aimthe most promising lead compounds will be evaluated in in vitro ADME assayse gsolubilitypermeabilitymicrosomal stabilityand in vitro toxicitye gCYPinhibitionAmes test and hERG inhibitionInhibitors of high interest will undergo in vivo pharmacokineticPKprofiling and exploratory toxicity testingAimis to test these lead compounds in our unique animal disease models for long term efficacy at blocking fructose induced fatty livernonalcoholic fatty liver diseaseand metabolic syndromeas well the protection of mice with HFIdue to knockout of the aldolase B genetowards fructoseInhibitors with robust efficacy will also be evaluated in exploratory toxicology studiesCompletion of these studies should result in an optimal preclinical development candidate for a first inclass drug for those suffering from HFI and metabolic syndrome We will develop a new class of low molecular weight agents to block fructokinase Ca critical enzyme target in fructose metabolismFructose metabolism mediates sugarand carbohydrate induced obesityfatty liverand insulin resistance diabetesInhibitors optimized for in vivo proof of mechanism and pharmacological efficacy will be used to design drugs with superior potency and specificity using X ray crystallography and design based on structures of co crystalsfollowed by chemical synthesisBlocking the adverse effects of sugar could impact the epidemic of obesity and diabetes