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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; et al.

(Profiled Authors: David T Chuang; Philipp E Scherer; Uttam K Tambar; Noelle S Williams; Richard M Wynn)

Journal of Biological Chemistry. 2014;289(7):4432-4443.


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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc..

PMID: 24356970     PMCID: PMC3924305    

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