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

J Med Chem. 2018 Sep 13;61(17):7785-7795. doi: 10.1021/acs.jmedchem.8b00765. Epub 2018 Aug 30.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Cycle Proteins / antagonists & inhibitors*
  • Drug Design*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / pathology
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Protein Conformation*
  • Protein Domains
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1