title: Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors.
abstract: 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 IC50(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.
authors.forename: Shih-Chia
authors.initials: SC
authors.lastname: Tso
authors.affiliation: 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.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Lou
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Wu
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Gui
authors.forename: Jacinta L
authors.initials: JL
authors.lastname: Chuang
authors.forename: Lorraine K
authors.initials: LK
authors.lastname: Morlock
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: R Max
authors.initials: RM
authors.lastname: Wynn
authors.affiliation: 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.
authors.forename: Xiangbing
authors.initials: X
authors.lastname: Qi
authors.forename: David T
authors.identifier: 0000-0002-3640-8927
authors.initials: DT
authors.lastname: Chuang
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; C000631433:Pdk1 protein, mouse; C000631435:Pdk2 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases