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Identification of Novel Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors by Kinase Activity-Based High-Throughput Screening for Anticancer Therapeutics
Zhang W.; Hu X.; Chakravarty H.; Yang Z.; Tam K.Y.
2018-11-12
Source PublicationACS Combinatorial Science
ISSN21568944 21568952
Volume20Issue:11Pages:660-671
AbstractWarburg effect, a preference of aerobic glycolysis for energy production even in the presence of adequate oxygen, is one of the most prominent distinctions of cancer cells from their normal equivalents. Upregulated pyruvate dehydrogenase kinase 1 (PDK1) was found to dominate the pivotal switch from mitochondrial respiration to aerobic glycolysis by inactivating pyruvate dehydrogenase (PDH) in cancer cells. PDK1 inhibition may lead to an unfavorable environment for cancer cells, which presents an opportunity for anticancer therapy. However, up to now, only limited number of PDK1 inhibitors were reported. In this work, we reported our attempt to discover novel small molecules from a diverse chemical library containing 15 000 small molecules selected from the Chembridge screening library. We developed a kinase activity-based high throughput screening (HTS) assay for initial screening of PDK1 inhibitors. Seven PDK1 inhibitory compounds were identified with IC values range from 0.68 and 45.69 μM. Follow up evaluations on these compounds revealed good PDK1 binding affinity and antiproliferative activities in cancer cell lines, with two novel hits (9 and 10) clearly outperformed others compounds in terms of PDK1 inhibition and the suppression of cancer cell proliferation. 9 and 10 may serve as new chemistry starting points for further structural modifications to improve the potency on PDK1 inhibition for anticancer treatment.
Keywordcancer high-throughput screening pyruvate dehydrogenase kinase 1 small molecule inhibitors Warburg effect
DOI10.1021/acscombsci.8b00104
URLView the original
Indexed BySCI
Language英語
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Applied ; Chemistry, Medicinal ; Chemistry, Multidisciplinary
WOS IDWOS:000450374200008
PublisherAMER CHEMICAL SOC
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Citation statistics
Document TypeJournal article
CollectionUniversity of Macau
AffiliationUniversidade de Macau
Recommended Citation
GB/T 7714
Zhang W.,Hu X.,Chakravarty H.,et al. Identification of Novel Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors by Kinase Activity-Based High-Throughput Screening for Anticancer Therapeutics[J]. ACS Combinatorial Science,2018,20(11):660-671.
APA Zhang W.,Hu X.,Chakravarty H.,Yang Z.,&Tam K.Y..(2018).Identification of Novel Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors by Kinase Activity-Based High-Throughput Screening for Anticancer Therapeutics.ACS Combinatorial Science,20(11),660-671.
MLA Zhang W.,et al."Identification of Novel Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors by Kinase Activity-Based High-Throughput Screening for Anticancer Therapeutics".ACS Combinatorial Science 20.11(2018):660-671.
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