Discovery and lead identification of quinazoline-based BRD4 inhibitors

Bioorg Med Chem Lett. 2018 Nov 15;28(21):3483-3488. doi: 10.1016/j.bmcl.2018.08.039. Epub 2018 Aug 31.

Abstract

A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.

Keywords: BET inhibitor; BRD4; Bromodomain; Cancer; Inflammation; Quinazoline.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Drug Discovery
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry

Substances

  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Quinazolines
  • Transcription Factors