Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1811-1816. doi: 10.1016/j.bmcl.2018.04.016. Epub 2018 Apr 10.


The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.

Keywords: BET; BRD4; Bromodomain inhibitors; Epigenetics; Fragment; Isoquinolinone.

MeSH terms

  • Binding Sites
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology
  • Molecular Dynamics Simulation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Isoquinolines
  • Nuclear Proteins
  • Transcription Factors