Abstract
Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.
Highlights
Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease
Fatty acid metabolism dysregulated through elevated fatty acid synthesis (FASyn), impaired fatty acid oxidation (FAOxn), or both is a hallmark of various metabolic disorders, including insulin resistance, hepatic steatosis, dyslipidemia, obesity, metabolic syndrome (MetSyn), and nonalcoholic fatty liver disease (NAFLD), that can lead to the development of type 2 diabetes (T2DM), nonalcoholic steatohepatitis (NASH), and atherosclerotic vascular disease [1,2,3,4,5,6]
In this report we describe the discovery and characterization of ND-630, a potent, highly specific, isozyme-nonselective, allosteric, protein–protein interaction ACC inhibitor that interacts within the phosphopeptide-acceptor and subunit dimerization site on the biotin carboxylase (BC) domain of both ACC1 and ACC2 to prevent dimerization and inhibit enzymatic activity
Summary
Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Initial studies with the long-chain fatty acid analog 5-(tetradecyloxy)-2-furancarboxylic acid [17, 18] and the isozyme-nonselective, active site-directed ACC inhibitor CP-640186 [1, 19] have demonstrated the potential for direct ACC inhibition to affect favorably a plethora of metabolic disorders. These pharmacologic studies have been supported further through genetic manipulation of ACC, including studies with ACC2-knockout mice [20, 21], ACC antisense oligonucleotides [22], TRB3 transgenic mice that have increased rates of ACC. ACC1 is a cytosolic enzyme present in lipogenic tissues
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