UM
Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation
Xiang,Sichuan1; Huang,Ding1; He,Qiaolin1; Li,Jie1; Tam,Kin Yip2; Zhang,Shao Lin1; He,Yun1
2020-10-01
Source PublicationEuropean Journal of Medicinal Chemistry
ISSN0223-5234
Volume203
AbstractMost cancer cells feature an altered glucose metabolism from oxidative phosphorylation to cytoplasmic glycolysis. Pyruvate dehydrogenase kinases (PDKs) and lactate dehydrogenase A (LDHA) play crucial roles in promotion of glycolysis, thus the inhibition of both enzymes is considered a promising strategy for developing of anticancer therapeutics. Herein, we describe the first discovery of series novel dual inhibitors targeting PDKs and LDHA. We identified 6 hits from a library database containing 485465 compounds through a high-throughput virtual screening assay. Hit-to-lead optimization enabled us to discover two compounds, namely 20e and 20k, which inhibited PDKs with IC values of 0.8, and 1.6 μM, respectively, and inhibited LDHA with IC values of 0.15 and 0.7 μM, respectively. Meanwhile, the two compounds reduced A549 cell proliferation with EC values of 13.2, and 15.7 μM. Furthermore, 20e and 20k decreased the lactate formation, and increased oxygen consumption, suggesting the two compounds modulated the glucose metabolic pathways in cancer cells.
KeywordCancer metabolism Cancer proliferation Dual inhibitor Lactate dehydrogenase A Pyruvate dehydrogenase kinase
DOI10.1016/j.ejmech.2020.112579
URLView the original
Language英语
Fulltext Access
Citation statistics
Cited Times [WOS]:2   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorHe,Yun
Affiliation1.School of Pharmaceutical Sciences,Chongqing Key Laboratory of Natural Product Synthesis and Drug Research,Chongqing University,Chongqing,401331,China
2.Faculty of Health Sciences,University of Macau,Taipa, Macau,China
Recommended Citation
GB/T 7714
Xiang,Sichuan,Huang,Ding,He,Qiaolin,et al. Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation[J]. European Journal of Medicinal Chemistry,2020,203.
APA Xiang,Sichuan,Huang,Ding,He,Qiaolin,Li,Jie,Tam,Kin Yip,Zhang,Shao Lin,&He,Yun.(2020).Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation.European Journal of Medicinal Chemistry,203.
MLA Xiang,Sichuan,et al."Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation".European Journal of Medicinal Chemistry 203(2020).
Files in This Item:
There are no files associated with this item.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Xiang,Sichuan]'s Articles
[Huang,Ding]'s Articles
[He,Qiaolin]'s Articles
Baidu academic
Similar articles in Baidu academic
[Xiang,Sichuan]'s Articles
[Huang,Ding]'s Articles
[He,Qiaolin]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Xiang,Sichuan]'s Articles
[Huang,Ding]'s Articles
[He,Qiaolin]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.