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

Yubai Zhou, Sandip Mukherjee, Daowei Huang, Molee Chakraborty, Chunfang Gu, Guangning Zong, Michael A. Stashko, Kenneth H. Pearce, Stephen B. Shears, Anutosh Chakraborty, Huanchen Wang, Xiaodong Wang

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Pages (from-to)6869-6887
Number of pages19
JournalJournal of Medicinal Chemistry
Volume65
Issue number9
DOIs
StatePublished - 2022

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