Publication

Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site

Masini, T., Birkaya, B., van Dijk, S., Mondal, M., Hekelaar, J., Jager, M., van Scheltinga, A. C. T., Patel, M. S., Hirsch, A. K. H. & Moman, E., 2016, In : Journal of enzyme inhibition and medicinal chemistry. 31 (S4), p. 170-175 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Masini, T., Birkaya, B., van Dijk, S., Mondal, M., Hekelaar, J., Jager, M., ... Moman, E. (2016). Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site. Journal of enzyme inhibition and medicinal chemistry, 31 (S4), 170-175. https://doi.org/10.1080/14756366.2016.1201812

Author

Masini, Tiziana ; Birkaya, Barbara ; van Dijk, Simon ; Mondal, Milon ; Hekelaar, Johan ; Jager, Manuel ; van Scheltinga, Anke C. Terwisscha ; Patel, Mulchand S. ; Hirsch, Anna K. H. ; Moman, Edelmiro. / Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site. In: Journal of enzyme inhibition and medicinal chemistry. 2016 ; Vol. 31 (S4). pp. 170-175.

Harvard

Masini, T, Birkaya, B, van Dijk, S, Mondal, M, Hekelaar, J, Jager, M, van Scheltinga, ACT, Patel, MS, Hirsch, AKH & Moman, E 2016, 'Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site', Journal of enzyme inhibition and medicinal chemistry, vol. 31 (S4), pp. 170-175. https://doi.org/10.1080/14756366.2016.1201812

Standard

Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site. / Masini, Tiziana; Birkaya, Barbara; van Dijk, Simon; Mondal, Milon; Hekelaar, Johan; Jager, Manuel; van Scheltinga, Anke C. Terwisscha; Patel, Mulchand S.; Hirsch, Anna K. H.; Moman, Edelmiro.

In: Journal of enzyme inhibition and medicinal chemistry, Vol. 31 (S4), 2016, p. 170-175.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Masini T, Birkaya B, van Dijk S, Mondal M, Hekelaar J, Jager M et al. Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site. Journal of enzyme inhibition and medicinal chemistry. 2016;31 (S4):170-175. https://doi.org/10.1080/14756366.2016.1201812


BibTeX

@article{76919835c6d643a6a56d90c7f9175723,
title = "Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site",
abstract = "The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.",
keywords = "Cancer metabolism, DCA, dichloroacetate, PDC, PDK2 inhibitors, pyruvate, CANCER-CELLS, METABOLISM, DICHLOROACETATE, MECHANISMS, PHOSPHORYLATION, HYPOXIA, COMPLEX",
author = "Tiziana Masini and Barbara Birkaya and {van Dijk}, Simon and Milon Mondal and Johan Hekelaar and Manuel Jager and {van Scheltinga}, {Anke C. Terwisscha} and Patel, {Mulchand S.} and Hirsch, {Anna K. H.} and Edelmiro Moman",
year = "2016",
doi = "10.1080/14756366.2016.1201812",
language = "English",
volume = "31 (S4)",
pages = "170--175",
journal = "Journal of enzyme inhibition and medicinal chemistry",
issn = "1475-6366",
publisher = "TAYLOR & FRANCIS LTD",

}

RIS

TY - JOUR

T1 - Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site

AU - Masini, Tiziana

AU - Birkaya, Barbara

AU - van Dijk, Simon

AU - Mondal, Milon

AU - Hekelaar, Johan

AU - Jager, Manuel

AU - van Scheltinga, Anke C. Terwisscha

AU - Patel, Mulchand S.

AU - Hirsch, Anna K. H.

AU - Moman, Edelmiro

PY - 2016

Y1 - 2016

N2 - The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.

AB - The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.

KW - Cancer metabolism

KW - DCA

KW - dichloroacetate

KW - PDC

KW - PDK2 inhibitors

KW - pyruvate

KW - CANCER-CELLS

KW - METABOLISM

KW - DICHLOROACETATE

KW - MECHANISMS

KW - PHOSPHORYLATION

KW - HYPOXIA

KW - COMPLEX

U2 - 10.1080/14756366.2016.1201812

DO - 10.1080/14756366.2016.1201812

M3 - Article

VL - 31 (S4)

SP - 170

EP - 175

JO - Journal of enzyme inhibition and medicinal chemistry

JF - Journal of enzyme inhibition and medicinal chemistry

SN - 1475-6366

ER -

ID: 40179068