2. Academic Validation
  3. Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions

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

  • J Med Chem. 2022 May 12;65(9):6869-6887. doi: 10.1021/acs.jmedchem.2c00220.
Yubai Zhou 1,  Sandip Mukherjee 2,  Daowei Huang 1,  Molee Chakraborty 2,  Chunfang Gu 3,  Guangning Zong 3,  Michael A Stashko 1,  Kenneth H Pearce 1,  Stephen B Shears 3,  Anutosh Chakraborty 2,  Huanchen Wang 3,  Xiaodong Wang 1 4
Affiliations

Affiliations

  • 1 Center 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.
  • 2 Department of Pharmacology and Physiology, Saint Louis University School of Medicine, M370, Schwitalla Hall, 1402 South Grand Boulevard, Saint Louis, Missouri 63104, United States.
  • 3 Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, United States.
  • 4 Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 35467861 DOI: 10.1021/acs.jmedchem.2c00220
Abstract

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.

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