Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain

J Med Chem. 2018 May 24;61(10):4317-4334. doi: 10.1021/acs.jmedchem.7b01666. Epub 2018 May 3.

Abstract

The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Cycle Proteins
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Quantitative Structure-Activity Relationship
  • Quinoxalines / chemistry*
  • Quinoxalines / pharmacology*
  • Sequence Homology
  • Transcription Factors / antagonists & inhibitors*

Substances

  • BRD2 protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Quinoxalines
  • Transcription Factors
  • Protein Serine-Threonine Kinases