Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains

J Med Chem. 2016 Jun 9;59(11):5391-402. doi: 10.1021/acs.jmedchem.6b00264. Epub 2016 May 31.

Abstract

The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.

MeSH terms

  • Binding Sites / drug effects
  • Cell Cycle Proteins
  • Dose-Response Relationship, Drug
  • Fluorescence Resonance Energy Transfer
  • Fluorometry
  • Histone Acetyltransferases / antagonists & inhibitors*
  • Histone Acetyltransferases / metabolism
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • TATA-Binding Protein Associated Factors / antagonists & inhibitors*
  • TATA-Binding Protein Associated Factors / metabolism
  • Transcription Factor TFIID / antagonists & inhibitors*
  • Transcription Factor TFIID / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Water / chemistry*

Substances

  • 6-methyl pyrrolopyridone
  • BRD4 protein, human
  • BRD9 protein, human
  • Cecr2 protein, human
  • Cell Cycle Proteins
  • Ligands
  • Nuclear Proteins
  • Pyridones
  • Pyrroles
  • TAF2 protein, human
  • TATA-Binding Protein Associated Factors
  • Transcription Factor TFIID
  • Transcription Factors
  • Water
  • Histone Acetyltransferases
  • TATA-binding protein associated factor 250 kDa