Tso Shih-Chia, Lou Mingliang, Wu Cheng-Yang, Gui Wen-Jun, Chuang Jacinta L, Morlock Lorraine K, Williams Noelle S, Wynn R Max, Qi Xiangbing, Chuang David T
Chemistry Center, National Institute of Biological Science , Beijing 102206, China.
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100730, China.
J Med Chem. 2017 Feb 9;60(3):1142-1150. doi: 10.1021/acs.jmedchem.6b01540. Epub 2017 Jan 31.
Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide (17) shows a ∼8-fold lower IC (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.
丙酮酸脱氢酶激酶1-4（PDK1-4）对丙酮酸脱氢酶复合体（PDC）的活性起负调控作用，且在肥胖、糖尿病、心力衰竭和癌症中上调。我们之前报道了两种新型的泛PDK抑制剂PS8 [4-((5-羟基异吲哚啉-2-基)磺酰基)苯-1,3-二醇]（1）和PS10 [2-((2,4-二羟基苯基)磺酰基)异吲哚啉-4,6-二醇]（2），它们靶向PDKs中的ATP结合口袋。在此，我们通过将1和2中的二羟基苯基磺酰基异吲哚啉支架延伸至PDK2中ATP结合口袋的入口区域，开发了新一代的PDK抑制剂。先导抑制剂（S）-3-氨基-4-(4-((2-((2,4-二羟基苯基)磺酰基)异吲哚啉-5-基)氨基)哌啶-1-基)-4-氧代丁酰胺（17）的IC50（58 nM）比2（456 nM）低约8倍。在晶体结构中，17中的天冬酰胺部分与PDK2的Glu-262有额外的相互作用。用17处理饮食诱导的肥胖小鼠导致肝脏特异性的PDC活性显著增强，同时糖耐量改善，肝脂肪变性明显减轻。这些发现支持17作为一种潜在的针对肥胖和2型糖尿病肝脏的降糖治疗药物。
