Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-03, Vol.113 (13), p.E1796-E1805
• Main Authors: Harriman, Geraldine, Greenwood, Jeremy, Bhat, Sathesh, Huang, Xinyi, Wang, Ruiying, Paul, Debamita, Tong, Liang, Saha, Asish K., Westlin, William F., Kapeller, Rosana, Harwood, H. James
• Format: Article
• Language: English
• Subjects: Acetyl-CoA Carboxylase - antagonists & inhibitors; Acetyl-CoA Carboxylase - metabolism; Animals; Biological Sciences; Dyslipidemias - drug therapy; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Fatty acids; Fatty Liver - drug therapy; Female; Glucose; Hemoglobin; Hep G2 Cells - drug effects; Hep G2 Cells - metabolism; Humans; Insulin Resistance; Liver diseases; Male; Molecular Docking Simulation; Obesity - drug therapy; Obesity - etiology; Oxidation; PNAS Plus; Protein Multimerization - drug effects; Pyrimidinones - pharmacology; Rats, Sprague-Dawley; Rats, Zucker; RNA-protein interactions; Structure-Activity Relationship; Thiophenes - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1520686113

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.