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Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and Heat Shock Protein 90

文献类型：期刊论文

作者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
出版日期2014-12-11
卷号57期号:23页码:9832-9843
ISSN号0022-2623
DOI10.1021/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.
WOS关键词BIOLOGICAL EVALUATION ; CANCER-CELLS ; LUNG-CANCER ; HYPOXIA ; DERIVATIVES ; EXPRESSION ; DICHLOROACETATE ; PHOSPHORYLATION ; ADAPTATION ; METABOLISM
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000346321200009
出版者AMER CHEMICAL SOC
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.

入库方式： OAI收割

来源：上海药物研究所

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