Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors

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.

doi:10.1021/acs.jmedchem.6b01540

Title: Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors

Journal Article · Fri Jan 13 00:00:00 EST 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b01540· OSTI ID:1343990

Tso, Shih-Chia ^[1]; Lou, Mingliang ^[2]; Wu, Cheng-Yang ^[1]; Gui, Wen-Jun ^[1]; Chuang, Jacinta L. ^[1]; Morlock, Lorraine K. ^[1]; Williams, Noelle S. ^[1]; Wynn, R. Max ^[1]; Qi, Xiangbing ^[2];

^[1]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Chinese Academy of Medical Sciences, Beijing (China); National Inst. of Biological Science, Beijing (China)

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. Furthermore, these findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); I-1286

Grant/Contract Number:: DK62306; 2014CB849603

OSTI ID:: 1343990

Journal Information:: Journal of Medicinal Chemistry, Vol. 60, Issue 3; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 21 works

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References (36)

Metabolic fuel selection: general integration at the whole-body level Randle, Philip J. Proceedings of the Nutrition Society, Vol. 54, Issue 1 https://doi.org/10.1079/PNS19950057	journal	March 1995
Regulation of the activity of the pyruvate dehydrogenase complex Harris, Robert A.; Bowker-Kinley, Melissa M.; Huang, Boli Advances in Enzyme Regulation, Vol. 42 https://doi.org/10.1016/S0065-2571(01)00061-9	journal	January 2002
Molecular biology and biochemistry of pyruvate dehydrogenase complexes ¹ Patel, Mulchand S.; Roche, Thomas E. The FASEB Journal, Vol. 4, Issue 14 https://doi.org/10.1096/fasebj.4.14.2227213	journal	November 1990
Reduced PDK4 Expression Associates with Increased Insulin Sensitivity in Postobese Patients Rosa, Giuseppina; Di Rocco, Paola; Manco, Melania Obesity Research, Vol. 11, Issue 2 https://doi.org/10.1038/oby.2003.28	journal	February 2003
Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice Jeoung, Nam Ho; Harris, Robert A. American Journal of Physiology-Endocrinology and Metabolism, Vol. 295, Issue 1 https://doi.org/10.1152/ajpendo.00536.2007	journal	July 2008
Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes Wu, P.; Inskeep, K.; Bowker-Kinley, M. M. Diabetes, Vol. 48, Issue 8 https://doi.org/10.2337/diabetes.48.8.1593	journal	August 1999
Regulation of branched-chain amino acid catabolism in rat models for spontaneous type 2 diabetes mellitus Kuzuya, Teiji; Katano, Yoshiaki; Nakano, Isao Biochemical and Biophysical Research Communications, Vol. 373, Issue 1 https://doi.org/10.1016/j.bbrc.2008.05.167	journal	August 2008
FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate Piao, Lin; Sidhu, Vaninder K.; Fang, Yong-Hu Journal of Molecular Medicine, Vol. 91, Issue 3 https://doi.org/10.1007/s00109-012-0982-0	journal	December 2012
HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia Kim, Jung-whan; Tchernyshyov, Irina; Semenza, Gregg L. Cell Metabolism, Vol. 3, Issue 3 https://doi.org/10.1016/j.cmet.2006.02.002	journal	March 2006
A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence Kaplon, Joanna; Zheng, Liang; Meissl, Katrin Nature, Vol. 498, Issue 7452 https://doi.org/10.1038/nature12154	journal	May 2013
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption Papandreou, Ioanna; Cairns, Rob A.; Fontana, Lucrezia Cell Metabolism, Vol. 3, Issue 3 https://doi.org/10.1016/j.cmet.2006.01.012	journal	March 2006
PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice: effect of PDH kinase 1 compensation Dunford, Emily C.; Herbst, Eric A.; Jeoung, Nam Ho American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 300, Issue 6 https://doi.org/10.1152/ajpregu.00498.2010	journal	June 2011
Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice Jeoung, Nam Ho; Rahimi, Yasmeen; Wu, Pengfei Biochemical Journal, Vol. 443, Issue 3 https://doi.org/10.1042/BJ20112197	journal	April 2012
A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth Bonnet, Sébastien; Archer, Stephen L.; Allalunis-Turner, Joan Cancer Cell, Vol. 11, Issue 1 https://doi.org/10.1016/j.ccr.2006.10.020	journal	January 2007
Tyrosine Phosphorylation of Mitochondrial Pyruvate Dehydrogenase Kinase 1 Is Important for Cancer Metabolism Hitosugi, Taro; Fan, Jun; Chung, Tae-Wook Molecular Cell, Vol. 44, Issue 6 https://doi.org/10.1016/j.molcel.2011.10.015	journal	December 2011
Metabolic Effects of Dichloroacetate in Patients with Diabetes Mellitus and Hyperlipoproteinemia Stacpoole, Peter W.; Moore, George W.; Kornhauser, David M. New England Journal of Medicine, Vol. 298, Issue 10 https://doi.org/10.1056/NEJM197803092981002	journal	March 1978
PDK1 inhibition is a novel therapeutic target in multiple myeloma Fujiwara, S.; Kawano, Y.; Yuki, H. British Journal of Cancer, Vol. 108, Issue 1 https://doi.org/10.1038/bjc.2012.527	journal	November 2012
Treatment of congenital lactic acidosis with dichloroacetate Stacpoole, P. W.; Barnes, C. L.; Hurbanis, M. D. Archives of Disease in Childhood, Vol. 77, Issue 6 https://doi.org/10.1136/adc.77.6.535	journal	December 1997
Mito-DCA: A Mitochondria Targeted Molecular Scaffold for Efficacious Delivery of Metabolic Modulator Dichloroacetate Pathak, Rakesh K.; Marrache, Sean; Harn, Donald A. ACS Chemical Biology, Vol. 9, Issue 5 https://doi.org/10.1021/cb400944y	journal	March 2014
Diisopropylamine Dichloroacetate, a Novel Pyruvate Dehydrogenase Kinase 4 Inhibitor, as a Potential Therapeutic Agent for Metabolic Disorders and Multiorgan Failure in Severe Influenza Yamane, Kazuhiko; Indalao, Irene L.; Chida, Junji PLoS ONE, Vol. 9, Issue 5 https://doi.org/10.1371/journal.pone.0098032	journal	May 2014
AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats Mayers, R. M.; Butlin, R. J.; Kilgour, E. Biochemical Society Transactions, Vol. 31, Issue 6 https://doi.org/10.1042/bst0311165	journal	December 2003
Secondary Amides of (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic Acid as Inhibitors of Pyruvate Dehydrogenase Kinase Aicher, Thomas D.; Anderson, Robert C.; Gao, Jiaping Journal of Medicinal Chemistry, Vol. 43, Issue 2 https://doi.org/10.1021/jm990358+	journal	December 1999
Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops Kato, Masato; Wynn, R. Max; Chuang, Jacinta L. Structure, Vol. 16, Issue 12 https://doi.org/10.1016/j.str.2008.10.010	journal	December 2008
Pyruvate Dehydrogenase Kinase-4 Structures Reveal a Metastable Open Conformation Fostering Robust Core-free Basal Activity Wynn, R. Max; Kato, Masato; Chuang, Jacinta L. Journal of Biological Chemistry, Vol. 283, Issue 37 https://doi.org/10.1074/jbc.M802249200	journal	September 2008
Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun Journal of Biological Chemistry, Vol. 289, Issue 7 https://doi.org/10.1074/jbc.M113.533885	journal	February 2014
VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells Moore, Jonathan D.; Staniszewska, Anna; Shaw, Terence Oncotarget, Vol. 5, Issue 24 https://doi.org/10.18632/oncotarget.2656	journal	November 2014
JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification Sun, Wenyi; Xie, Zuoquan; Liu, Yifu Cancer Research, Vol. 75, Issue 22 https://doi.org/10.1158/0008-5472.CAN-15-1023	journal	October 2015
GHKL, an emergent ATPase/kinase superfamily Dutta, R.; Inouye, M. Trends in Biochemical Sciences, Vol. 25, Issue 1 https://doi.org/10.1016/S0968-0004(99)01503-0	journal	January 2000
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays Baell, Jonathan B.; Holloway, Georgina A. Journal of Medicinal Chemistry, Vol. 53, Issue 7 https://doi.org/10.1021/jm901137j	journal	April 2010
Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex Kato, Masato; Chuang, Jacinta L.; Tso, Shih-Chia The EMBO Journal, Vol. 24, Issue 10 https://doi.org/10.1038/sj.emboj.7600663	journal	April 2005
Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics Wagner, David J.; Hu, Tao; Wang, Joanne Pharmacological Research, Vol. 111 https://doi.org/10.1016/j.phrs.2016.06.002	journal	September 2016
Flux through hepatic pyruvate carboxylase and phosphoenolpyruvate carboxykinase detected by hyperpolarized 13C magnetic resonance Merritt, M. E.; Harrison, C.; Sherry, A. D. Proceedings of the National Academy of Sciences, Vol. 108, Issue 47 https://doi.org/10.1073/pnas.1111247108	journal	November 2011
Liver-Targeted Prodrugs of 2‘- C -Methyladenosine for Therapy of Hepatitis C Virus Infection Hecker, Scott J.; Reddy, K. Raja; van Poelje, Paul D. Journal of Medicinal Chemistry, Vol. 50, Issue 16 https://doi.org/10.1021/jm0701021	journal	July 2007
FAF-Drugs3: a web server for compound property calculation and chemical library design Lagorce, David; Sperandio, Olivier; Baell, Jonathan B. Nucleic Acids Research, Vol. 43, Issue W1 https://doi.org/10.1093/nar/gkv353	journal	April 2015
Integration and global analysis of isothermal titration calorimetry data for studying macromolecular interactions Brautigam, Chad A.; Zhao, Huaying; Vargas, Carolyn Nature Protocols, Vol. 11, Issue 5 https://doi.org/10.1038/nprot.2016.044	journal	April 2016
Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain -ketoacid dehydrogenase kinase Tso, S. -C.; Qi, X.; Gui, W. -J. Proceedings of the National Academy of Sciences, Vol. 110, Issue 24 https://doi.org/10.1073/pnas.1303220110	journal	May 2013

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Title: Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors

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