JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification
文献类型：期刊论文
| 作者 | Sun, Wenyi2; Xie, Zuoquan2 ; Liu, Yifu3; Zhao, Dan1; Wu, Zhixiang4; Zhang, Dadong2; Lv, Hao2; Tang, Shuai2; Jin, Nan2; Jiang, Hualiang1
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| 刊名 | CANCER RESEARCH
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| 出版日期 | 2015-11-15 |
| 卷号 | 75期号:22页码:4923-4936 |
| ISSN号 | 0008-5472 |
| DOI | 10.1158/0008-5472.CAN-15-1023 |
| 文献子类 | Article |
| 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. |
| WOS关键词 | PROTEIN-KINASE ; CANCER-CELLS ; PYRUVATE-DEHYDROGENASE-KINASE-2 ; DICHLOROACETATE ; MITOCHONDRIA ; METABOLISM ; EXPRESSION ; AZD7545 ; HYPOXIA ; COMPLEX |
| 资助项目 | National Program on Key Basic Research Project of China[2012CB910704] ; National Natural Science Foundation of China[81222049] ; National Natural Science Foundation of China[21222211] ; National Natural Science Foundation of China[81202549] ; Natural Science Foundation of China for Innovation Research Group[81321092] ; Actelion Pharmaceuticals Ltd.[00000000] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| 出版者 | AMER ASSOC CANCER RESEARCH |
| WOS记录号 | WOS:000365602600024 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276321]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药理学第一研究室 |
| 通讯作者 | Geng, Meiyu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Chem Prote Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Sun, Wenyi,Xie, Zuoquan,Liu, Yifu,et al. JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification[J]. CANCER RESEARCH,2015,75(22):4923-4936. |
| APA | Sun, Wenyi.,Xie, Zuoquan.,Liu, Yifu.,Zhao, Dan.,Wu, Zhixiang.,...&Geng, Meiyu.(2015).JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification.CANCER RESEARCH,75(22),4923-4936. |
| MLA | Sun, Wenyi,et al."JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification".CANCER RESEARCH 75.22(2015):4923-4936. |
入库方式： OAI收割
来源：上海药物研究所
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