Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket

Shih Chia Tso, Xiangbing Qi, Wen Jun Gui, Cheng Yang Wu, Jacinta L. Chuang, Ingrid Wernstedt-Asterholm, Lorraine K. Morlock, Kyle R. Owens, Philipp E. Scherer, Noelle S. Williams, Uttam K. Tambar, R. Max Wynn, David T. Chuang

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Background: Up-regulated pyruvate dehydrogenase kinase isoforms (PDKs) are associated with impaired glucose homeostasis in diabetes. Results: Novel PDK inhibitors were developed using structure-based design, which improves glucose tolerance with reduced hepatic steatosis in diet-induced obese mice. Conclusion: Obesity phenotypes are effectively treated by chemical intervention with PDK inhibitors. Significance: PDKs are potential drug targets for obesity and type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)4432-4443
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number7
DOIs
StatePublished - Feb 14 2014

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Medical problems
Obesity
Adenosine Triphosphate
Glucose
Obese Mice
Nutrition
Type 2 Diabetes Mellitus
Protein Isoforms
Homeostasis
Diet
Phenotype
Liver
Pharmaceutical Preparations
pyruvate dehydrogenase (acetyl-transferring) kinase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. / Tso, Shih Chia; Qi, Xiangbing; Gui, Wen Jun; Wu, Cheng Yang; Chuang, Jacinta L.; Wernstedt-Asterholm, Ingrid; Morlock, Lorraine K.; Owens, Kyle R.; Scherer, Philipp E.; Williams, Noelle S.; Tambar, Uttam K.; Wynn, R. Max; Chuang, David T.

In: Journal of Biological Chemistry, Vol. 289, No. 7, 14.02.2014, p. 4432-4443.

Research output: Contribution to journalArticle

Tso, Shih Chia ; Qi, Xiangbing ; Gui, Wen Jun ; Wu, Cheng Yang ; Chuang, Jacinta L. ; Wernstedt-Asterholm, Ingrid ; Morlock, Lorraine K. ; Owens, Kyle R. ; Scherer, Philipp E. ; Williams, Noelle S. ; Tambar, Uttam K. ; Wynn, R. Max ; Chuang, David T. / Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 7. pp. 4432-4443.
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