Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and Heat Shock Protein 90 | |
Meng, Tao1; Zhang, Dadong2; Xie, Zuoquan2; Yu, Ting1; Wu, Shuchao2; Wyder, Lorenza3; Regenass, Urs3; Hilpert, Kurt3; Huang, Min2; Geng, Meiyu2 | |
刊名 | JOURNAL OF MEDICINAL CHEMISTRY |
2014-12-11 | |
卷号 | 57期号:23页码:9832-9843 |
ISSN号 | 0022-2623 |
DOI | 10.1021/jm5010144 |
文献子类 | Article |
英文摘要 | Upregulation of pyruvate dehydrogenase kinase (PDHK) has been observed in a variety of cancers. Inhibition of PDHK offers an attractive opportunity for the development of novel cancer therapies. To obtain novel PDHK inhibitors, we took advantage of the homology of the ATP-binding pocket between Heat Shock Protein 90 (HSP90) and PDHK, and utilized 4,5-diarylisoxazole based HSP90 inhibitor for structural design. Our efforts led to the identification of 5k that inhibited PDHK1 with an IC50 value of 17 nM, which, however, showed marginal cellular activity. Further structural optimization resulted in compound 11a with improved cellular activity which could effectively modulate the metabolic profile of cancer cells and lead to the inhibition of cancer cell proliferation, evidenced by the increased oxidative phosphorylation and decreased glycolysis and associated oxidative stress. Our results suggested 11a as an excellent lead compound and a favorable biological tool to further evaluate the therapeutic potential of PDHK and HSP90 dual inhibitors in the treatment of cancer. |
资助项目 | Ministry of Science and Technology of China[2012ZX09301001-007] ; National Natured Science Foundation of China[81202549] ; National Natural Science Foundation of China[81222049] ; Shanghai Metropolitan Government[12PJ1410400] ; Actelion Pharmaceuticals Ltd.[00000000] |
WOS关键词 | BIOLOGICAL EVALUATION ; CANCER-CELLS ; LUNG-CANCER ; HYPOXIA ; DERIVATIVES ; EXPRESSION ; DICHLOROACETATE ; PHOSPHORYLATION ; ADAPTATION ; METABOLISM |
WOS研究方向 | Pharmacology & Pharmacy |
语种 | 英语 |
出版者 | AMER CHEMICAL SOC |
WOS记录号 | WOS:000346321200009 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/276806] |
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 药物化学研究室 |
通讯作者 | Huang, Min |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Med Chem, Shanghai 201203, 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.Actelion Pharmaceut, CH-4123 Allschwil, Switzerland |
推荐引用方式 GB/T 7714 | Meng, Tao,Zhang, Dadong,Xie, Zuoquan,et al. Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and Heat Shock Protein 90[J]. JOURNAL OF MEDICINAL CHEMISTRY,2014,57(23):9832-9843. |
APA | Meng, Tao.,Zhang, Dadong.,Xie, Zuoquan.,Yu, Ting.,Wu, Shuchao.,...&Shen, Jingkang.(2014).Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and Heat Shock Protein 90.JOURNAL OF MEDICINAL CHEMISTRY,57(23),9832-9843. |
MLA | Meng, Tao,et al."Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and Heat Shock Protein 90".JOURNAL OF MEDICINAL CHEMISTRY 57.23(2014):9832-9843. |
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