Preclinical Efficacy of INST3399, a Synthetic Novel PKCbeta Inhibitor, for the Treatment of Obesity and Fatty Liver Disease. (14th June 2022)

• Record Type: Journal Article
• Authors: Mehta, Kamal
• Is Part Of: Current developments in nutrition. Volume 6(2022)Supplement 1
• Page Start: 1076
• Page End: 1076
• Publication Date: 2022-06-14
• Subjects: Nutrition -- Periodicals; Nutritional Physiological Phenomena; Nutrition; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 612.3
• DOI: 10.1093/cdn/nzac070.035
• Languages: English
• ISSNs: 2475-2991

Abstract

Abstract: Objectives: The prevalence of obesity has increased over the last few decades reaching epidemic proportions. Clearly, public health efforts and anti obesity agents presently in use are inadequate for curbing the obesity epidemic. Currently existing FDA-approved anti-obesity drugs are specific receptor-targeted drugs that focus on reducing energy intake. Energy intake reduction is equivalent to calorie-restricted dieting and is prone to weight cycling because it decreases muscle mass, leading to reduced metabolic function and energy expenditure. Hence, long-term weight loss is difficult to achieve. In consideration of the aforementioned hurdles, a promising anti-obesity drug should consist of multi-functional effects leading to energy expenditure. We previously demonstrated that mice with systemic PKCβ deficiency displayed many of the features one would desire in individuals treated with an ideal anti-obesity drug; elevated metabolic rate, which contribute to protection from diet-induced obesity, hepatic steatosis, and insulin-resistance (Hepatology 49:1525, 2009; J. Lipid Res. 286:22, 795, 2011). We recently reported that depletion of hepatocyte-specific PKCβ recapitulates many of the beneficial features of systemic PKCbeta deficient mice (Mol. Metab. 44: e101133, 2021; JCI Insight 6: e149023, 2021). These results provide compelling evidence that PKCβ is an important therapeutic target for the treatment of obesity, as well as its related metabolic complications. Methods: Our aim is to evaluate therapeutic effects of a novel PKCβ inhibitor, INST3399 to treat obesity and fatty liver disease in a high-fat diet-induced obese C57BL/6J mouse model. Results: INST3399 is a novel PKCβ inhibitor, which inhibits this kinase by a mechanism different from a well-known alternative ruboxistaurin. INST3399 inhibits PKCβ in the basal state, about >5-times more potent than ruboxistaurin and exhibit more than >100-fold selectivity for PKCβ versus PKCα. Our data demonstrate that INST3399 is safe and able to decrease the degree of obesity and fatty liver disease. Conclusions: INST3399 is a promising novel drug candidate for the pharmacological treatment of obesity and associated comorbidities. Moreover, INST3399 could further evolve as a novel treatment to manage other metabolic conditions with excessive PKCβ expression. Funding Sources: NIH HL138198; Instacare Funds.