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

doi:10.1074/jbc.M113.533885

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 journal › Article › peer-review

86 Scopus citations

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 language	English (US)
Pages (from-to)	4432-4443
Number of pages	12
Journal	Journal of Biological Chemistry
Volume	289
Issue number	7
DOIs	https://doi.org/10.1074/jbc.M113.533885
State	Published - Feb 14 2014

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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Tso, S. C., Qi, X., Gui, W. J., Wu, C. Y., Chuang, J. L., Wernstedt-Asterholm, I., Morlock, L. K., Owens, K. R., Scherer, P. E., Williams, N. S., Tambar, U. K., Wynn, R. M., & Chuang, D. T. (2014). Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. Journal of Biological Chemistry, 289(7), 4432-4443. https://doi.org/10.1074/jbc.M113.533885

Tso, SC, Qi, X, Gui, WJ, Wu, CY, Chuang, JL, Wernstedt-Asterholm, I, Morlock, LK, Owens, KR, Scherer, PE , Williams, NS , Tambar, UK , Wynn, RM & Chuang, DT 2014, 'Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket', Journal of Biological Chemistry, vol. 289, no. 7, pp. 4432-4443. https://doi.org/10.1074/jbc.M113.533885

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title = "Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket",

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.",

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

year = "2014",

month = feb,

day = "14",

doi = "10.1074/jbc.M113.533885",

language = "English (US)",

volume = "289",

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AU - Tso, Shih Chia

AU - Qi, Xiangbing

AU - Gui, Wen Jun

AU - Wu, Cheng Yang

AU - Chuang, Jacinta L.

AU - Wernstedt-Asterholm, Ingrid

AU - Morlock, Lorraine K.

AU - Owens, Kyle R.

AU - Scherer, Philipp E.

AU - Williams, Noelle S.

AU - Tambar, Uttam K.

AU - Wynn, R. Max

AU - Chuang, David T.

PY - 2014/2/14

Y1 - 2014/2/14

N2 - 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.

AB - 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.

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

Abstract

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