The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling

Abstract

Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We previously discovered that the inositol pyrophosphate biosynthetic enzyme IP6K1 is a target in diet-induced obesity (DIO), insulin resistance, and NAFLD. Moreover, high-throughput screening (HTS) assays and structure−activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO WT C57/BL6J mice. LI-2242 (20 mg/kg/BW daily, i.p.) reduced body weight in DIO mice by specifically reducing the accumulation of body fat. It also improved glycemic parameters and reduced hyperinsulinemia. LI-2242-treated mice displayed reduced the weight of various adipose tissue depots and an increased expression of metabolism- and mitochondrial-energy-oxidation-inducing genes in these tissues. LI-2242 also ameliorated hepatic steatosis by reducing the expression of genes that enhance lipid uptake, lipid stabilization, and lipogenesis. Furthermore, LI-2242 enhances the mitochondrial oxygen consumption rate (OCR) and insulin signaling in adipocytes and hepatocytes in vitro. In conclusion, the pharmacologic inhibition of the inositol pyrophosphate pathway by LI-2242 has therapeutic potential in obesity and NAFLD.

The Role of Inositol Hexakisphosphate Kinase in the Central Nervous System

“…To date, the only known inhibitors of IP6Ks do not cross the blood–brain barrier (BBB). Furthermore, the most potent of these inhibitors are not isoform selective [ 24 , 32 , 33 , 35 , 136 ]. Currently, no structural information is known about the three mammalian IP6K isoforms aside from the AlphaFold predicted structures.…”

Kcs1 and Vip1: The Key Enzymes behind Inositol Pyrophosphate Signaling in Saccharomyces cerevisiae

“…Conversely, the deletion of IP6K1 offered protection to insulin resistance and reduced high-fat-diet obesity and fatty liver in mice. A successful disturbance of the PP-IP pathway by selective inhibitors for IP6Ks [72,73] was reported in mice, showing ameliorated symptoms of obesity, fatty liver, and insulin resistance [70].…”

Identification and Characterization of a Blood–Brain Barrier Penetrant Inositol Hexakisphosphate Kinase (IP6K) Inhibitor

“…Prior work has identified very potent IP6K inhibitors that rely on a carboxylic acid for exquisite potency and kinome selectivity exemplified by compounds 1 – 3 (Figure ). ,, Compound 1 was recently published by a group at UNC . We previously disclosed compound 2 which was developed by a high-throughput screening hit .…”