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

doi:10.1021/jm5010144

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and Heat Shock Protein 90
	Meng, Tao1 ; Zhang, Dadong 2; Xie, Zuoquan2 ; Yu, Ting 1; Wu, Shuchao 2; Wyder, Lorenza 3; Regenass, Urs 3; Hilpert, Kurt 3; 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.