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

Yubai Zhou1, Sandip Mukherjee2, Daowei Huang1

  • 1Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Journal of Medicinal Chemistry
|April 25, 2022
PubMed

Insights

A novel inhibitor targeting inositol hexakisphosphate kinase (IP6K) effectively reduced obesity-related metabolic issues in mice. This compound shows promise for treating obesity and associated diseases.

Area of Science:

  • Biochemistry
  • Metabolic Diseases
  • Pharmacology

Background:

  • Obesity and associated metabolic dysfunctions are major risk factors for nonalcoholic fatty liver disease and cardiovascular diseases, posing a significant burden.
  • Inositol hexakisphosphate kinase (IP6K) plays a role in inositol pyrophosphate synthesis, and its inhibition is a potential therapeutic strategy for obesity.
  • Developing potent and selective IP6K inhibitors is crucial for exploring therapeutic applications.

Purpose of the Study:

  • To develop and characterize a novel, potent inhibitor of IP6K.
  • To evaluate the effects of the inhibitor on inositol pyrophosphate levels in vitro.
  • To assess the in vivo efficacy of the inhibitor in a diet-induced obesity mouse model.

Main Methods:

  • Synthesis and biochemical characterization of IP6K inhibitor 20 (UNC7467).
  • Inositol phosphate profiling in HCT116 colon cancer cells treated with inhibitor 20.
  • Administration of inhibitor 20 to diet-induced obese mice via intraperitoneal injection.

Main Results:

  • Inhibitor 20 demonstrated high potency against IP6K1 and IP6K2 (IC50 values 8.9 nM and 4.9 nM, respectively).
  • Treatment with inhibitor 20 significantly reduced inositol pyrophosphate levels by 66-81% in vitro without affecting other inositol phosphates.
  • In vivo studies showed that inhibitor 20 improved glycemic profiles, reduced hepatic steatosis, and decreased weight gain in obese mice without impacting food intake.

Conclusions:

  • Inhibitor 20 is a potent and selective IP6K inhibitor with significant in vitro and in vivo activity.
  • This compound serves as a valuable in vivo probe for IP6K-related research.
  • Inhibitor 20 holds therapeutic potential for the treatment of obesity and related metabolic diseases.

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