5J71

Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PS35

Summary for 5J71

• Entry DOI: 10.2210/pdb5j71/pdb
• Related: 4MP2 4MP7 4MPC 4MPE 4MPN 5J6A
• Descriptor: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial, L(+)-TARTARIC ACID, 4-({5-[(piperidin-4-yl)amino]-1,3-dihydro-2H-isoindol-2-yl}sulfonyl)benzene-1,3-diol, ... (4 entities in total)
• Functional Keywords: ghkl protein kinase, pyruvate dehydrogenase complex, mitochondrial protein kinases, impaired glucose oxidation, hepatic steatosis, type 2 diabetes, cancer, bergerat nucleotide-binding fold, protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 45772.96

Authors

Gui, W.J.,Tso, S.C.,Chuang, J.L.,Wu, C.Y.,Qi, X.,Wynn, R.M.,Chuang, D.T. (deposition date: 2016-04-05, release date: 2017-01-25, Last modification date: 2023-09-27)

Primary citation

Tso, S.C.,Lou, M.,Wu, C.Y.,Gui, W.J.,Chuang, J.L.,Morlock, L.K.,Williams, N.S.,Wynn, R.M.,Qi, X.,Chuang, D.T.
Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors.
J. Med. Chem., 60:1142-1150, 2017

PubMed 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 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.

PubMed: 28085286
DOI: 10.1021/acs.jmedchem.6b01540

Experimental method

X-RAY DIFFRACTION (1.65 Å)