Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

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 inh...

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Published inJournal of medicinal chemistry Vol. 61; no. 17; pp. 7785 - 7795
Main Authors Liu, Shuai, Yosief, Hailemichael O, Dai, Lingling, Huang, He, Dhawan, Gagan, Zhang, Xiaofeng, Muthengi, Alex M, Roberts, Justin, Buckley, Dennis L, Perry, Jennifer A, Wu, Lei, Bradner, James E, Qi, Jun, Zhang, Wei
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.09.2018
Amer Chemical Soc
Subjects
Cell Cycle Proteins - antagonists & inhibitors
Chemistry, Medicinal
Drug Design
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - enzymology
Leukemia, Myeloid, Acute - pathology
Life Sciences & Biomedicine
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Nuclear Proteins - antagonists & inhibitors
Pharmacology & Pharmacy
Polo-Like Kinase 1
Protein Conformation
Protein Domains
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein Serine-Threonine Kinases - antagonists & inhibitors
Proto-Oncogene Proteins - antagonists & inhibitors
Science & Technology
Structure-Activity Relationship
Transcription Factors - antagonists & inhibitors
Tumor Cells, Cultured
TARGET
CHEMICAL PROBE
FORCE-FIELD
PROTEIN BRD4
EPIGENOME
SYNERGISTIC ACTIVITY
BETS
PLACE
CANCER-THERAPY
P-TEFB
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Summary: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.
Bibliography:NIH RePORTER
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00765