Abstract
The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Cell Cycle Proteins / antagonists & inhibitors*
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Drug Design*
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / enzymology
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Leukemia, Myeloid, Acute / pathology
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Models, Molecular
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Molecular Docking Simulation
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Molecular Structure
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Nuclear Proteins / antagonists & inhibitors*
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Polo-Like Kinase 1
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Protein Conformation*
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Protein Domains
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors*
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Tumor Cells, Cultured
Substances
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BRD4 protein, human
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Cell Cycle Proteins
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Nuclear Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Transcription Factors
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Protein Serine-Threonine Kinases