4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines

J Med Chem. 2020 Dec 24;63(24):15603-15620. doi: 10.1021/acs.jmedchem.0c00478. Epub 2020 Dec 4.


Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI50 determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromosomal Proteins, Non-Histone / antagonists & inhibitors*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Crystallography, X-Ray
  • Humans
  • Kinetics
  • Ligands
  • Molecular Dynamics Simulation
  • Protein Domains
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Pyrroles / chemistry*
  • Pyrroles / metabolism
  • Pyrroles / pharmacology
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism


  • Antineoplastic Agents
  • BRD7 protein, human
  • BRD9 protein, human
  • Chromosomal Proteins, Non-Histone
  • Ligands
  • Proteins
  • Pyrroles
  • Transcription Factors
  • bromodomain and extra-terminal domain protein, human