文献类型：期刊文献

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

作者：Liu, Yifu[1];Xie, Zuoquan[2];Zhao, Dan[3];Zhu, Jin[1];Mao, Fei[1];Tang, Shuai[2];Xu, Hui[2];Luo, Cheng[3];Geng, Meiyu[2];Huang, Min[2];Li, Jian[1]

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

年份：2017

卷号：60

期号：6

起止页码：2227

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000397546000006)】；

基金：Financial support of this research provided by the National Natural Science Foundation of China (grants 21672064, 21372001, 81573464), the "Shu Guang" project supported by the Shanghai Municipal Education Commission and the Shanghai Education Development Foundation (grant 14SG28), and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.

语种：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.