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Anticancer effects of some novel dichloroacetophenones through the inhibition of pyruvate dehydrogenase kinase 1
Zhang, Shao-Lin1; Yang, Zheng1; Hu, Xiaohui2; Chakravarty, Harapriya1; Tam, Kin Yip1
2018-10-15
Source PublicationEUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
ISSN0928-0987
Volume123Pages:43-55
Abstract

Targeting pyruvate dehydrogenase kinase 1 (PDK1) has been suggested as a potential anticancer strategy. 2,2-dichloroacetophenone (DAP) is a PDK1 inhibitor exhibiting weak anticancer potency and poor selectivity. The current study describes the characterization of three potent compounds 54, 55 and 64, which tightly bound to PDK1 with K-d values of 1.29, 0.97, and 0.58 mu M, respectively, and activated pyruvate dehydrogenase complex with EC50 values of 0.68, 0.49, and 0.33 mu M, respectively. In contrast with DAP, these analogues were more potent and selective against PDK1, reduced proliferation and survival of NCI-H1975 cells, and suppressed tumor growth in a NCI-H1975 xenograft mouse model. Moreover, compounds 54, 55 and 64 depolarized mitochondrial membrane potential, induced cell apoptosis, decreased extracellular lactate formation, and increased reactive oxygen species production in NCI-H1975 cells. They may serve as potential modulators to regulate mitochondrial function and reprogram metabolism in cancer cells which could represent promising compounds for further development of potent PDK1 inhibitors.

KeywordDichloroacetophenone Pyruvate Dehydrogenase Kinase Pyruvate Dehydrogenase Complex Anticancer Activity Metabolic Reprogramming
DOIhttp://doi.org/10.1016/j.ejps.2018.07.026
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000443566100005
PublisherELSEVIER SCIENCE BV
The Source to ArticleWOS
Fulltext Access
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorTam, Kin Yip
Affiliation1.Faculty of Health Sciences, University of Macau, Taipa, Macau, China
2.Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Zhang, Shao-Lin,Yang, Zheng,Hu, Xiaohui,et al. Anticancer effects of some novel dichloroacetophenones through the inhibition of pyruvate dehydrogenase kinase 1[J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,2018,123:43-55.
APA Zhang, Shao-Lin,Yang, Zheng,Hu, Xiaohui,Chakravarty, Harapriya,&Tam, Kin Yip.(2018).Anticancer effects of some novel dichloroacetophenones through the inhibition of pyruvate dehydrogenase kinase 1.EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,123,43-55.
MLA Zhang, Shao-Lin,et al."Anticancer effects of some novel dichloroacetophenones through the inhibition of pyruvate dehydrogenase kinase 1".EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 123(2018):43-55.
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