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
Nimbus Therapeutics, Cambridge, MA 02141;
Schrodinger Inc., New York, NY 10036;
Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1796-805. doi: 10.1073/pnas.1520686113. Epub 2016 Mar 14.
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.
同时抑制乙酰辅酶A羧化酶(ACC)的同工酶ACC1和ACC2会导致脂肪酸合成受到抑制,同时脂肪酸氧化受到刺激,这可能对肥胖、糖尿病和脂肪肝疾病相关的发病率和死亡率产生有利影响。通过基于结构的药物设计,我们鉴定出了一系列有效的变构蛋白-蛋白相互作用抑制剂,以ND-630为代表,它们在ACC磷酸肽受体和二聚化位点内相互作用,以防止二聚化并抑制两种ACC同工酶的酶活性,减少培养细胞和动物体内的脂肪酸合成并刺激脂肪酸氧化,并且具有良好的类药物特性。当长期给予饮食诱导肥胖的大鼠时,ND-630可减轻肝脏脂肪变性,改善胰岛素敏感性,减少体重增加而不影响食物摄入量,并对血脂异常产生有利影响。当长期给予Zucker糖尿病脂肪大鼠时,ND-630可减轻肝脏脂肪变性,改善葡萄糖刺激的胰岛素分泌,并降低糖化血红蛋白(降低0.9%)。总之,这些数据表明该系列代表物对ACC的抑制作用可能有助于治疗多种代谢紊乱,包括代谢综合征、2型糖尿病和脂肪肝疾病。