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Development of the First Generation of Disulfide-Based Subtype Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors

文献类型：期刊论文

作者Liu, Yifu2; Xie, Zuoquan1; Zhao, Dan3; Zhu, Jin2; Mao, Fei2; Tang, Shuai1; Xu, Hui1; Luo, Cheng3; Geng, Meiyu1; Huang, Min1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2017-03-23
卷号60期号:6页码:2227-2244
ISSN号0022-2623
DOI10.1021/acs.jmedchem.6b01245
文献子类Article
英文摘要Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (k(mact)/K-i = 4.17 x 10(3) M-1 s(-1)) and the cellular level (down to 0.1 mu M). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.
WOS关键词CANCER METABOLISM ; ORPHAN DRUG ; IN-VIVO ; DICHLOROACETATE ; PYRUVATE-DEHYDROGENASE-KINASE-2 ; PHOSPHORYLATION ; ADAPTATION ; MECHANISMS ; EXPRESSION ; AZD7545
资助项目National Natural Science Foundation of China[21672064] ; National Natural Science Foundation of China[21372001] ; National Natural Science Foundation of China[81573464] ; "Shu Guang" project - Shanghai Municipal Education Commission[00000000] ; Shanghai Education Development Foundation[14SG28] ; Fundamental Research Funds for the Central Universities[00000000]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000397546000006
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/272736]  
专题药理学第一研究室
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
通讯作者Huang, Min; Li, Jian
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
2.East 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, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Yifu,Xie, Zuoquan,Zhao, Dan,et al. Development of the First Generation of Disulfide-Based Subtype Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(6):2227-2244.
APA Liu, Yifu.,Xie, Zuoquan.,Zhao, Dan.,Zhu, Jin.,Mao, Fei.,...&Li, Jian.(2017).Development of the First Generation of Disulfide-Based Subtype Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,60(6),2227-2244.
MLA Liu, Yifu,et al."Development of the First Generation of Disulfide-Based Subtype Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 60.6(2017):2227-2244.

入库方式： OAI收割

来源：上海药物研究所

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