文献类型：期刊文献

英文题名：JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification

作者：Sun, Wenyi[1];Xie, Zuoquan[1];Liu, Yifu[2];Zhao, Dan[3];Wu, Zhixiang[4];Zhang, Dadong[1];Lv, Hao[1];Tang, Shuai[1];Jin, Nan[1];Jiang, Hualiang[3];Tan, Minjia[4];Ding, Jian[1];Luo, Cheng[3];Li, Jian[2];Huang, Min[1];Geng, Meiyu[1]

机构：[1]Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[4]Chinese Acad Sci, Shanghai Inst Mat Med, Chem Prote Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2015

卷号：75

期号：22

起止页码：4923

外文期刊名：CANCER RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000365602600024)】；

基金：This work was supported by the National Program on Key Basic Research Project of China (No. 2012CB910704 to M. Geng), grants from National Natural Science Foundation of China (No. 81222049 to M. Huang, No. 21222211 to J. Li, and No. 81202549 to Z. Xie), and the Natural Science Foundation of China for Innovation Research Group (No. 81321092 to J. Ding). The PDK enzymatic assay was established with the financial support by Actelion Pharmaceuticals Ltd.

语种：英文

摘要：Pyruvate dehydrogenase kinase PDK1 is a metabolic enzyme responsible for switching glucose metabolism from mitochondrial oxidation to aerobic glycolysis in cancer cells, a general hallmark of malignancy termed the Warburg effect. Herein we report the identification of JX06 as a selective covalent inhibitor of PDK1 in cells. JX06 forms a disulfide bond with the thiol group of a conserved cysteine residue (C240) based on recognition of a hydrophobic pocket adjacent to the ATP pocket of the PDK1 enzyme. Our investigations of JX06 mechanism suggested that covalent modification at C240 induced conformational changes at Arginine 286 through Van der Waals forces, thereby hindering access of ATP to its binding pocket and in turn impairing PDK1 enzymatic activity. Notably, cells with a higher dependency on glycolysis were more sensitive to PDK1 inhibition, reflecting a metabolic shift that promoted cellular oxidative stress and apoptosis. Our findings offer new mechanistic insights including how to therapeutically target PDK1 by covalently modifying the C240 residue. (C) 2015 AACR.