Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site.
Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site.
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DOI：
10.1080/14756366.2016.1201812
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发表时间：
2016
影响因子：
5.6
通讯作者：
Moman E
中科院分区：
文献类型：
--
作者：
Masini T;Birkaya B;van Dijk S;Mondal M;Hekelaar J;Jäger M;Terwisscha van Scheltinga AC;Patel MS;Hirsch AK;Moman E
在过去的十年中，癌症代谢作为治疗靶点的地位再次被唤醒。特别是，抑制丙酮酸脱氢酶激酶（PDK）具有显著的前景。目前正在进行临床试验的二氯乙酸（DCA）是一种独特的PDK抑制剂，它与酶的变构丙酮酸位点结合。然而，DCA作为药物的安全性受到其神经毒性的影响，而其作为研究工具的有用性受到在细胞培养中发挥可观察到的作用所需的高浓度的限制。在这里，我们报告的识别-通过利用饱和转移差NMR光谱，酶测定和计算方法-糠酸和thenoate衍生物作为别构丙酮酸位点结合PDK 2抑制剂。这项工作证实了丙酮酸调节口袋作为一个可药用的目标。
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.
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影响因子：
4.8
作者：
KOROTCHKINA, LG;PATEL, MS
通讯作者：
PATEL, MS
影响因子：
2.9
作者：
Knoechel, TR;Tucker, AD;Brown, DG
通讯作者：
Brown, DG
影响因子：
4.8
作者：
Li, Jun;Kato, Masato;Chuang, David T.
通讯作者：
Chuang, David T.
DOI：
10.1021/jp8111556
发表时间：
2009-05-14
期刊：
The journal of physical chemistry. A
影响因子：
--
作者：
Mantina M;Chamberlin AC;Valero R;Cramer CJ;Truhlar DG
通讯作者：
Truhlar DG
影响因子：
17.1
作者：
Michelakis, E. D.;Sutendra, G.;Petruk, K. C.
通讯作者：
Petruk, K. C.