Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions br

Obesity and obesity-induced metabolic dysfunctions are significant risk factors for nonalcoholic fatty liver diseaseand cardiovascular diseases. Thus, obesity is an economic andsocial burden in developed countries. Blocking the synthesis ofinositol pyrophosphates by inositol hexakisphosphate kinase(IP6K) has been identified as a potential therapeutic strategy forobesity and related diseases. We have developed a novel andpotent IP6K inhibitor20(UNC7467) (IC50values: IP6K1 8.9nM; IP6K2 4.9 nM; IP6K3 1320 nM). Inositol phosphate profilingof the HCT116 colon cancer cell line demonstrates that20reduced levels of inositol pyrophosphates by 66-81%, withoutsignificantly perturbing levels of other inositol phosphates. Furthermore, intraperitoneal injection of20in diet-induced obese miceimproved glycemic profiles, ameliorated hepatic steatosis, and reduced weight gain without altering food intake. Thus, inhibitor20can be used as anin vivoprobe for IP6K-related research. Moreover, it may have therapeutic relevance in treating obesity and related diseases