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    • In HepG cells compound showed inhibition of total

    2023-10-25

    In HepG2 cells, tankyrase showed inhibition of total lipid syntheses with an IC of 8μM. A cell based Alamar Blue cytotoxicity assay was used in parallel to differentiate the effect on the inhibition of lipid synthesis versus potential cytotoxicity. Under identical incubation conditions, compound showed no cytotoxicity up to 50μM, indicating the observed inhibition of lipid synthesis was not a result of compound-induced cytotoxicity. To assess if compound was suitable for oral dosing, a standard pharmacokinetic assessment was performed. In mice, showed an oral bioavailability of 55% but a relatively short half-life of 2.1h. We therefore decided to dose admixed in the food to assure greater duration of exposure in subsequent chronic efficacy studies. In contrast to the reported hypolipidemic effect of compound in normal fed rats, no clear trend for lipid lowering or hepatic lipid synthesis inhibition was observed when compound was dosed chronically in mice that were fed a chow diet (data not shown). We subsequently examined the effect of in high-fat fed mice, a model which more closely mimics typical western dietary intake. There were a total of four groups in the study; mice on normal diet and high-fat diet controls, and two treated groups that were supplemented with in their high-fat diet to an equivalent daily dose of 10 or 100mg/kg. The study was continued for a total of 34days. Food consumption and body weight gain were tracked along with weekly assessment of lipid and glucose plasma chemistries. As shown in , there was a modest lowering of both plasma cholesterol and triglycerides after 20days of treatment. A reduction in fasting plasma glucose was observed from day 7 to completion of the study. At day 29, cholesterol was lowered by 19% with the 100mg/kg dose and triglycerides were lowered by 26% in both the 10 and 100mg/kg treatment groups. Fasting plasma glucose was lowered by 48% and 32% for 10 and 100mg/kg doses, respectively, as summarized in . The high-fat diet produced a 13.8% weight gain over the course of the study while mice on normal diet for the same length of time gained 7.8% ( and ). The 10 and 100mg/kg treatment groups gained only 7.2% and 3.0%, respectively, from their starting weights. Relative to high-fat fed controls, treatment with 10mg/kg of showed a trend toward decreased weight gain, whereas it became significant at the 100mg/kg dose (). Importantly, no apparent changes in food consumption among high-fat fed groups were observed, indicating that the reduction in body weight gain and lipid/glucose parameters was not attributed simply to a difference in food intake between the treated groups. Additionally, no overt toxicities, including changes in locomotor activity, plasma transaminases or liver composition, were observed in any group (data not shown). Body composition was determined by DEXA analysis at the completion of the study ( and ). As expected, mice on the high-fat diet exhibited a significant increase in adiposity as compared to the normal fed group (13.7% body weight as fat for normal diet vs 25.4% body weight as fat for high-fat diet group, an 85% increase; ). In contrast, the 10mg/kg treatment resulted in a comparable fat composition to the lean, normal-chow fed control, while the 100mg/kg group experienced a 71% reduction in adiposity relative to high-fat control. The epididymal fat pads from these mice were also weighed, and the reduction in adiposity was qualitatively similar to the results from the DEXA analysis. Furthermore, a reduction of fat tissue was seen across several anatomical areas including the neck, kidney, and in the subcutaneous depot (data not shown). In summary, we have identified a 2-hydroxy--arylbenzenesulfonamide as a cell-permeable ACL inhibitor with modest potency. When administered to mice fed on a high-fat diet at 10 and 100mg/kg/day, it produced an approximate 20–30% lowering in plasma cholesterol and triglycerides, as well as a 30–50% decrease in fasting plasma glucose. More intriguingly, chronic treatment with showed a gradual inhibition of weight gain along with a reduction in adiposity without apparent changes in food intake. Using this high-fat diet mouse model, our preliminary results suggest that inhibition of ACL results in improved lipid and glycemic profiles as well as decreased adipogenesis, ultimately leading to a reduction in body weight gain. However, future studies will be required to clarify the mechanism and probe the role of ACL in the regulation of metabolic pathway and its therapeutic potential.