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

Obesity and obesity-induced metabolic
dysfunctions are significant
risk factors for nonalcoholic fatty liver disease and cardiovascular
diseases. Thus, obesity is an economic and social burden in developed
countries. Blocking the synthesis of inositol pyrophosphates by inositol
hexakisphosphate kinase (IP6K) has been identified as a potential
therapeutic strategy for obesity and related diseases. We have developed
a novel and potent IP6K inhibitor 20 (UNC7467) (IC50 values: IP6K1 8.9 nM; IP6K2 4.9 nM; IP6K3 1320 nM). Inositol
phosphate profiling of the HCT116 colon cancer cell line demonstrates
that 20 reduced levels of inositol pyrophosphates by
66–81%, without significantly perturbing levels of other inositol
phosphates. Furthermore, intraperitoneal injection of 20 in diet-induced obese mice improved glycemic profiles, ameliorated
hepatic steatosis, and reduced weight gain without altering food intake.
Thus, inhibitor 20 can be used as an in vivo probe for IP6K-related research. Moreover, it may have therapeutic
relevance in treating obesity and related diseases.